5-aryl-4,5-dihydro-(1H)-pyrazolines as cannabinoid CB1 receptor agonists

ABSTRACT

The invention is directed to 5-(hetero)aryl-4,5-dihydro-(1H)-pyrazole (pyrazoline) derivatives as cannabinoid CB 1  receptor agonists, to pharmaceutical compositions comprising these compounds, to methods for their syntheses, methods for preparing novel intermediates useful for their syntheses, and methods for preparing compositions. The invention also relates to the uses of such compounds and compositions, administered to patients to achieve a therapeutic effect in disorders in which CB 1  receptors are involved, or that can be treated via manipulation of those receptors. 
     Compounds of the present invention include compounds of formula (I): 
                         
wherein the substituents have the definitions given in the specification.

This application claims the benefit of U.S. provisional application No.60/973,863, filed Sep. 20, 2007, the disclosure of which is incoporatedherein by reference.

The present disclosure relates to the fields of pharmaceutical andorganic chemistry, and provides 5-(hetero)aryl-4,5-dihydro-(1H)-pyrazole(pyrazoline) derivatives, intermediates for synthesizing thesecompounds, formulations comprising these compounds, and methods oftreatment using these compounds.

The endogenous cannabinoid receptor agonist, anandamide, is too unstableto be of practical value as a drug. The same is true for otherendocannabinoids such as 2-arachidonoyl-glycerol and noladin ether. Withthe exception of Δ⁹-tetrahydrocannabinol (Δ⁹-THC, dronabinol, Marinol®)and Nabilone (Cesamet®) no other cannabinoid receptor agonists have beenregistered as drugs. In addition, Sativex® (an extract from the Cannabissativa L. plant) has been recently approved as a prescription medicine(Barnes, 2006). Compounds like CP 55,940 and WIN 55,212-2 are notregistered drugs, but have been, and still are, used as pharmacologicaltools.

It has been postulated that cannabinoid CB₁ receptors can occur in twodifferent states: the active ‘R*-state’ to which agonists bind, and theinactive ‘R-state’ to which antagonists or inverse agonists—such asrimonabant—bind. Both states have considerably differentthree-dimensional geometries. Key interaction in the cannabinoid-CB₁receptor model (based on Palczewski's X-ray structure of bovinerhodopsin) is a hydrogen bond between the carbonyl group of, e.g., theCB₁ receptor inverse agonist rimonabant, and the LYS192 residue of theCB₁ receptor. This hydrogen bond has a stabilizing effect on theLys192-Asp366 salt bridge of the intracellular end of the transmembranehelices 3 and 6. The existence of this specific salt bridge is inducedby a pronounced kink at Pro 358 in transmembrane helix 6, present in theinactive R-state of the receptor, but not in the active R*-state, whichis stabilized by CB₁ receptor agonist binding (Hurst, 2002; Shim, 2002;Reggio, 2003; Pertwee, 2005 and Lange, 2005). Thus, it is not possibleto apply structural features of known CB₁ receptor antagonists orinverse agonists to design novel CB₁ receptor agonists in astraightforward manner.

Ample evidence exists that cannabinoid receptor agonists havetherapeutic possibilities as appetite stimulants, enti-emetics,analgesics, anti-glaucoma agents (Croxford, 2003; Drysdale, 2003), tumorgrowth inhibitors (Ligresti, 2003), and agents for the treatment ofneurodegenerative disorders, including multiple sclerosis andAlzheimer's disease (Smith, 2004; Croxford, 2004).

Thus, there is a need to develop novel compounds with CB₁ receptoragonistic activity, structurally unrelated to known cannabinoid receptoragonists.

DISCLOSURE

Surprisingly, the inventors found that replacing the 1-aryl or1-heteroaryl group in 4,5-dihydro-pyrazole CB₁ receptor antagonistsdescribed in WO 2005/074920, WO 2005/077911 or WO 2007/009689 by anoptionally substituted alkyl moiety, resulted in novel compounds with ahigh affinity for CB₁ receptors, wherein these compounds may act as fullor partial agonists at CB₁ receptors. Moreover, most of these compoundsalso showed affinity for CB₂ receptors.

In one embodiment, the invention relates to compounds of formula (I):

or tautomers, stereoisomers, N-oxides, isotopically-labelled analogues,or pharmaceutically acceptable salts of any of the foregoing,wherein:

-   -   R₁ is chosen from:        -   C₃₋₁₀ linear alkyl, C₄₋₁₀ branched alkyl, C₄₋₁₀ alkenyl,            C₄₋₁₀ alkynyl, C₃₋₁₀-heteroalkyl, C₅₋₈-cycloalkyl-C₁₋₅-alky,            and C₅₋₈-heterocycloalkyl-C₁₋₅-alkyl, each of which may be            optionally substituted with 1-5 substituents, wherein the            substituents are the same or different, and are chosen from            methyl, ethyl, hydroxy, amino, cyano and fluoro,        -   aryl-C₁₋₃-alkyl, heteroaryl-C₁₋₃-alkyl,            aryl-C₁₋₃-heteroalkyl, and heteroaryl-C₁₋₃-heteroalkyl,            wherein the aryl and heteroaryl groups are optionally            substituted with 1-5 substituents Y, wherein each Y is the            same or different, and is chosen from C₁₋₃-alkyl,            C₁₋₃-alkoxy, hydroxy, halogen, trifluoromethyl,            trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-            or dialkyl(C₁₋₂)-amino, mono- or dialkyl(C₁₋₂)-amido,            (C₁₋₃)-alkyl sulfonyl, dimethylsulfamido,            C₁₋₃-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl,            cyano, carbamoyl, sulfamoyl, phenyl and acetyl, and        -   2-cyano-ethyl;    -   R₂ is chosen from aryl and heteroaryl, each of which may be        optionally substituted with 1-5 substituents Y as defined above;    -   R₃ is chosen from:        -   linear and branched C₃₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₅₋₁₀            bicycloalkyl, C₆₋₁₀ tricycloalkyl and C₈₋₁₁ tetracycloalkyl,            each of which may be optionally substituted with 1-5            substituents, wherein the substituents are the same or            different, and are chosen from methyl, ethyl, hydroxy,            amino, and fluoro,        -   C₃₋₈ cycloalkyl substituted with aryl and heteroaryl,            wherein the aryl and heteroaryl are optionally substituted            with 1-5 substituents Y as defined above,        -   2,2,2-trifluoroethyl and 2-fluoroethyl,        -   C₅₋₈ heterocycloalkyl, C₆₋₁₀ bicycloheteroalkyl, and C₇₋₁₀            tricycloheteroalkyl, each of which may be optionally            substituted with 1-5 substituents, wherein the substituents            are the same or different, and are chosen from methyl,            ethyl, hydroxy, amino and fluoro,        -   C₃₋₈ cycloalkyl-C₁₋₃-alkyl, C₅₋₁₀-bicycloalkyl-C₁₋₃-alkyl,            and C₆₋₁₀-tricycloalkyl-C₁₋₃-alkyl, each of which may be            optionally substituted with 1-5 substituents, wherein the            substituents are the same or different, and are chosen from            methyl, ethyl, hydroxy, amino and fluoro,        -   branched and linear C₃₋₈ heterocycloalkyl-C₁₋₃-alkyl, C₅₋₁₀            bicycloheteroalkyl-C₁₋₃-alkyl, and C₆₋₁₀            tricycloheteroalkyl-C₁₋₃-alkyl, each of which may be            optionally substituted with 1-5 substituents, wherein the            substituents are the same or different, and are chosen from            methyl, ethyl, hydroxy, amino and fluoro,        -   aryl and heteroaryl, each of which may be optionally            substituted with 1-5 substituents Y as defined above,        -   aryl-C₁₋₅-alkyl, heteroaryl-C₁₋₅-alkyl, and            diaryl-C₁₋₅-alkyl, wherein the aryl and heteroaryl groups            are optionally substituted with 1-5 substituents Y as            defined above,        -   linear and branched C₄₋₈ alkenyl and C₄₋₈ alkynyl, each of            which may be optionally substituted with 1-3 fluorine atoms,            and        -   branched and linear C₂₋₁₀ heteroalkyl, comprising 1-2            heteroatoms chosen from N, O, or S;    -   R₄ is chosen from hydrogen and C₁₋₄ alkyl;    -   R₅ is chosen from hydrogen and C₁₋₂ alkyl, optionally        substituted with 1-3 fluorine atoms; and    -   R₆ is chosen from hydrogen and C₁₋₂ alkyl, optionally        substituted with 1-3 fluorine atoms.

In another embodiment, the invention relates to compounds of formula(I):

or tautomers, stereoisomers, N-oxides, isotopically-labelled analogues,or pharmaceutically acceptable salts of any of the foregoing,wherein:

-   -   R₁ is chosen from:        -   C₃₋₁₀ linear alkyl, C₄₋₁₀ branched alkyl, and            C₅₋₈-cycloalkyl-C₁₋₅-alkyl, each of which may be optionally            substituted with 1-3 substituents, wherein the substituents            are the same or different, and are chosen from methyl,            ethyl, cyano, and fluoro,        -   aryl-C₁₋₃-alkyl, wherein the aryl group is optionally            substituted with 1-3 substituents Y, wherein each Y is the            same or different, and is chosen from C₁₋₃-alkyl,            C₁₋₃-alkoxy, halogen, trifluoromethyl, trifluoro-methoxy,            nitro, cyano, and phenyl, and        -   2-cyano-ethyl;    -   R₂ is chosen from phenyl, thienyl, benzothienyl, and pyridyl,        each of which may be optionally substituted with 1 or 2        substituents, wherein the substituents are the same or        different, and are chosen from halogen, methyl, CF₃, OCH₃, and        OCF₃;    -   R₃ is chosen from:        -   linear and branched C₃₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₅₋₁₀            bicycloalkyl, and C₆₋₁₀ tricycloalkyl, each of which may be            optionally substituted with 1-3 substituents, wherein the            substituents are the same or different, and are chosen from            methyl, ethyl, hydroxy, amino, fluoro and aryl,        -   C₅₋₈ heterocycloalkyl optionally substituted with 1-5            substituents, wherein the substituents are the same or            different, and are chosen from methyl, ethyl, and fluoro,        -   C₃₋₈ cycloalkyl-C₁₋₃-alkyl, C₅₋₁₀-bicycloalkyl-C₁₋₃-alkyl,            and C₆₋₁₀-tricycloalkyl-C₁₋₃-alkyl, each of which may be            optionally substituted with 1-5 substituents, wherein the            substituents are the same or different, and are chosen from            methyl, ethyl, and fluoro,        -   aryl and heteroaryl, each of which may be optionally            substituted with 1-5 substituents Y, wherein each Y is the            same or different, and is chosen from C₁₋₃-alkyl,            C₁₋₃-alkoxy, halogen, trifluoromethyl, trifluoromethylthio,            trifluoromethoxy, nitro, cyano, and phenyl,        -   aryl-C₁₋₅-alkyl, heteroaryl-C₁₋₅-alkyl, and            diaryl-C₁₋₅-alkyl, wherein the aryl and heteroaryl groups            are optionally substituted with 1-5 substituents, wherein            the substituents are the same or different, and are chosen            from C₁₋₃-alkyl, C₁₋₃-alkoxy, halogen, trifluoromethyl,            trifluoromethylthio, trifluoromethoxy, nitro, cyano, and            phenyl,        -   branched and linear C₂₋₁₀ heteroalkyl, comprising 1-2            heteroatoms chosen from N, O, and S; and    -   R₄, R₅, and R₆ are as defined above.

In another embodiment, the invention relates to compounds of formula(I):

or tautomers, stereoisomers, N-oxides, isotopically-labelled analogues,or pharmaceutically acceptable salts of any of the foregoing,wherein:

-   -   R₁ is chosen from:        -   C₃₋₈ linear alkyl, C₄₋₈ branched alkyl, and            C₅₋₆-cycloalkyl-C₁₋₅-alkyl, each of which may be optionally            substituted with 1-3 substituents, wherein the substituents            are the same or different, and are chosen from cyano and            fluoro,        -   aryl-C₁₋₃-alkyl and 2-cyano-ethyl;    -   R₂ is chosen from phenyl, thienyl, benzothienyl, and pyridyl,        each of which may be optionally substituted with halogen,        methyl, CF₃, OCH₃, and OCF₃; and    -   R₃, R₄, R₅, and R₆ are as defined above.

In another embodiment, the invention relates to compounds of formula(I):

or tautomers, stereoisomers, N-oxides, isotopically-labelled analogues,or pharmaceutically acceptable salts of any of the foregoing,wherein:

-   -   R₁ is chosen from 2-cyano-ethyl, n-propyl, n-butyl,        4,4,4-trifluorobutyl, isobutyl, n-pentyl, cyclohexylmethyl, and        phenethyl;    -   R₂ is chosen from 2-fluorophenyl, 3-(trifluoromethyl)phenyl,        3-chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-chlorophenyl,        4-fluorophenyl, benzothien-3-yl, pyrid-2-yl, thien-3-yl, and        phenyl;    -   R₃ is chosen from 3-(trifluoromethyl)benzyl,        3-(trifluoromethyl)benzyl, 1-(4-fluorophenyl)-1-methyl-ethyl,        1-phenyl-1-methyl-ethyl, 1-phenyl-ethyl, 2-indanyl,        2-(4-fluorophenyl)-1,1-dimethyl-ethyl,        2-(trifluoromethyl)benzyl, 2,2-dimethylpropyl,        2,2-diphenylethyl, 2,2-diphenylpropyl, 2-methoxybenzyl,        2-phenyl-propyl, 2-phenyl-trans-cyclopropyl,        2-trifluoromethyl)phenyl, 3,4,5-trimethoxybenzyl,        3,4-dimethoxybenzyl, 3-fluorobenzyl, 3-methoxybenzyl,        4-chlorobenzyl, 4-methoxybenzyl, 5-methyl-thiazol-2-yl,        adamant-1-yl, adamant-2-yl, adamantylmethyl, benzyl,        cycloheptyl, cyclohexylmethyl, cyclooctyl,        endo-bicyclo[2.2.1]hept-2-yl, exo-bicyclo[2.2.1]hept-2-yl,        indan-2-yl, N,2,2,6,6-pentamethylpiperidin-4-yl, naphth-1-yl,        naphthalen-1-yl-methyl, noradamant-1-yl, pyridin-3-ylmethyl,        quinolin-3-yl, tert-butyl, (1-ethyl)propyl,        (1R,2S,5R)-rel-6,6-dimethylbicyclo[3.1.1.]heptan-2-methyl,        (3-dimethylamino)-2,2-dimethylpropyl, (furan-2-yl)methyl,        (pyridin-3-yl)-methyl, 1-(4-fluorophenyl)-1-methyl-ethyl,        1-(adamant-1-yl)-ethyl, 1-phenyl-1-methyl-ethyl,        2-(4-fluorophenyl)ethyl, 2-(7-methyl-indol-3-yl)ethyl,        2-(indol-3-yl)ethyl, 2-(thien-2-yl)ethyl,        3-(trifluoromethyl)benzyl, 3,3-diphenylpropyl,        3,4-difluorobenzyl, 4-(trifluoromethyl)benzyl,        endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl,        naphthalen-1-yl-methyl, benzyl, cyclohexylmethyl, cyclopentyl,        methyl-N-(Naphthalen-1-yl-methyl), and phenyl;    -   R₄ is chosen from hydrogen and methyl;    -   R₅ is chosen from hydrogen and methyl; and    -   R₆ is hydrogen.

In another embodiment, the invention relates to compounds of formula(I):

or tautomers, stereoisomers, N-oxides, isotopically-labelled analogues,or pharmaceutically acceptable salts of any of the foregoing, whereinthe compounds of formula (I) are optically active enantiomers.

In a further embodiment, the invention relates to compounds of formula(I):

or tautomers, stereoisomers, N-oxides, isotopically-labelled analogues,or pharmaceutically acceptable salts of any of the foregoing, havingcannabinoid CB₁ receptor agonistic activity.

In a further embodiment, the invention relates to compounds of formula(I), or pharmaceutically acceptable salts thereof, for the treatment ofdisorders in which cannabinoid receptors are involved, and in addition,that can be treated via manipulation of those receptors.

In one embodiment, the invention relates to compounds of formula (I), orpharmaceutically acceptable salts thereof, for the treatment of multiplesclerosis, traumatic brain injury, pain including chronic pain,neuropathic pain, acute pain and inflammatory pain, osteoporosis,appetite disorders, epilepsy, Alzheimer's disease, Tourette's syndrome,cerebral ischaemia and gastrointestinal disorders.

Other embodiments of the invention include, but are not limited to:

pharmaceutical compositions for treating, for example, at least onedisorder or condition that may be treated by activating at least onecannabinoid CB₁ receptor, the compositions comprising a compound offormula (I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier;

methods of treatment of at least one disorder or condition that may betreated by activating at least one cannabinoid CB₁ receptor, the methodscomprising administering to a mammal in need of such treatment acompound of formula (I) or a pharmaceutically acceptable salt thereof;

pharmaceutical compositions for treating, for example, at least onedisorder or condition chosen multiple sclerosis, traumatic brain injury,pain including chronic pain, neuropathic pain, acute pain andinflammatory pain, osteoporosis, appetite disorders, epilepsy,Alzheimer's disease, Tourette's syndrome, cerebral ischaemia andgastrointestinal disorders;

methods of treatment of at least one disorder or condition chosen fromthe disorders listed herein, the methods comprising administering to amammal in need of such treatment a compound of formula (I) or apharmaceutically acceptable salt thereof;

pharmaceutical compositions for treatment of at least one disorder orcondition chosen from the disorders listed herein, the compositionscomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier;

methods of treatment of at least one disorder or condition that may betreated by activating at least one cannabinoid CB₁ receptor, the methodscomprising administering to a patient in need of such treatment acompound of formula (I) or a pharmaceutically acceptable salt thereof;and

methods of antagonizing at least one cannabinoid CB₁ receptor, whichcomprises administering to a subject in need thereof, an effectiveamount of a compound of formula (I).

The invention also provides for the use of at least one compound or saltaccording to formula (I) for the manufacture of a medicament.

The invention further relates to combination therapies wherein at leastone compound of the invention, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition or formulation comprising acompound of the invention, is administered concurrently or sequentiallyor as a combined preparation with another therapeutic agent or agents,for the treatment of one or more of the conditions listed. Such othertherapeutic agent(s) may be administered prior to, simultaneously with,or following the administration of the compounds of the invention.

The invention also provides compounds, pharmaceutical compositions, kitsand methods for the treatment of a disorder or condition that may betreated by activating at least one cannabinoid CB₁ receptor, the methodcomprising administering to a patient in need of such treatment acompound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention also provides methods of preparing the compounds of theinvention and the intermediates used in those methods.

Isolation and purification of the compounds and intermediates describedherein can be affected, if desired, by any suitable separation orpurification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography,thick-layer chromatography, preparative low or high-pressure liquidchromatography, or a combination of these procedures. Specificillustrations of suitable separation and isolation procedures can betaken from the preparations and examples. However, other equivalentseparation or isolation procedures could, of course, also be used.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers.

All compounds of the present invention do contain at least one chiralcenter (at the 5-position of the 4,5-dihydropyrazole ring). Additionalasymmetric centers may be present depending upon the nature of thevarious substituents on the molecule. Each such asymmetric center willindependently produce two optical isomers, and it is intended that allof the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within the ambit ofthis invention.

Cis and trans isomers of the compounds of formula (I) or ofpharmaceutically acceptable salts thereof are also within the scope ofthe invention, and this also applies to tautomers of the compounds offormula (I) or pharmaceutically acceptable salts thereof.

Some of the crystalline forms for the compounds may exist as polymorphs,and as such are intended to be included in the present invention. Inaddition, some of the compounds may form solvates with water (i.e.,hydrates) or common organic solvents, and such solvates are alsointended to be encompassed within the scope of this invention.

Isotopically-labeled compounds of formula (I) or pharmaceuticallyacceptable salts thereof, including compounds of formula (I)isotopically-labeled to be detectable by PET or SPECT, are also includedwithin the scope of the invention, and the same applies to compounds offormula (I) labeled with [¹³C]-, [¹⁴C]-, [³H]-, [¹⁸F]-, [¹²⁵I]- or otherisotopically enriched atoms, suitable for receptor binding or metabolismstudies.

The compounds of the invention may also be used as reagents or standardsin the biochemical study of neurological function, dysfunction anddisease.

DEFINITIONS

General terms used in the description of compounds herein disclosed beartheir usual meanings. The term alkyl as used herein denotes a univalentsaturated branched or straight hydrocarbon chain. Unless otherwisestated, such chains can contain from 1 to 18 carbon atoms.Representative of such alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl,undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,heptadecyl, octadecyl, and the like. When qualified as ‘lower’, thealkyl group will contain from 1 to 6 carbon atoms. The same carboncontent applies to the parent term ‘alkane’, and to derivative termssuch as ‘alkoxy’. The carbon content of various hydrocarbon containingmoieties is indicated by a prefix designating the minimum and maximumnumber of carbon atoms in the moiety, i.e., the prefix C_(x)-C_(y)defines the number of carbon atoms present from the integer “x” to theinteger “y” inclusive. ‘Alkyl(C₁₋₃)’ for example, means methyl, ethyl,n-propyl or isopropyl, and ‘alkyl(C₁₋₄)’ means ‘methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl’. The term‘alkenyl’ denotes straight or branched hydrocarbon radicals having oneor more carbon-carbon double bonds, such as vinyl, allyl, butenyl, etc.,and for example comprises (C₂₋₄)alkenyl. In ‘alkynyl’ groups thestraight or branched hydrocarbon radicals have one or more carbon-carbontriple bonds, such as ethynyl, propargyl, 1-butynyl, 2-butynyl, etc.,and e.g. includes (C₂₋₄)alkynyl. Unless otherwise stated, ‘alkenyl’ and‘alkynyl chains can contain from 1 to 18 carbon atoms.

The term ‘acyl’ comprises alkyl(C₁₋₃)carbonyl, arylcarbonyl oraryl-alkyl(C₁₋₃)carbonyl. ‘Aryl’ embraces mono- or polycyclic aromaticgroups, including phenyl, naphthyl, 1,2,3,4-tetrahydro-naphtyl, indenyl,fluorenyl, anthracenyl, phenanthrenyl, naphthacenyl and azulenyl.‘Heteroaryl’ embraces mono- or polycyclic hetero-aromatic, includingfuryl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,imidazo[2,1-b][1,3]thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl,indazolyl, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl,1,2,3,4-tetrahydroiso-quinolinyl, indanyl, indenyl, benzo[b]thienyl,2,3-dihydro-1,4-benzodioxin-5-yl, benzimidazolyl, cinnolinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,benzothiazolyl, benzo[1,2,5]thia-diazolyl, purinyl, quinolinyl,isoquinolinyl, quinolizinyl, phtalazinyl, quinazolinyl, quinoxalinyl,1,8-naphthyridinyl and pteridinyl.

‘Halo’ or ‘Halogen’ means chloro, fluoro, bromo or iodo; ‘hetero’ as in‘heteroalkyl, heteroaromatic’ etc. means containing one or more N, O orS atoms. ‘heteroalkyl’ includes alkyl groups with heteroatoms in anyposition, thus including N-bound O-bound or S-bound alkyl groups.

The term “substituted” means that the specified group or moiety bearsone or more substituents. Where any group may carry multiplesubstituents, and a variety of possible substituents is provided, thesubstituents are independently selected, and need not to be the same.The term “unsubstituted” means that the specified group bears nosubstituents. With reference to substituents, the term “independently”means that when more than one of such substituents are possible, theymay be the same or different from each other.

‘C₃₋₈-cycloalkyl’ means cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl; ‘C₅₋₈ heterocycloalkyl’ refers toheteroatom containing rings including but not limited to piperidinyl,morpholinyl, azepanyl, pyrrolidinyl, thiomorpholinyl, piperazinyl,tetrahydrofuryl, tetrahydropyranyl; ‘C₅₋₁₀ bicycloalkyl group’ refers tocarbo-bicyclic ring systems including but not limited tobicyclo[2.2.1]heptanyl, bicyclo[3.3.0]octanyl or thebicyclo[3.1.1]heptanyl group; ‘C₆₋₁₀ tricycloalkyl group’ refers tocarbo-tricyclic ring systems including but not limited to the1-adamantyl, noradamantyl or the 2-adamantyl group. The abbreviation‘C₈₋₁₁ tetracycloalkyl group’ refers to carbo-tetracyclic ring systemsincluding but not limited to the cubyl, homocubyl or bishomocubyl group.

The terms “oxy”, “thio” and “carbo” as used herein as part of anothergroup respectively refer to an oxygen atom, a sulphur atom and acarbonyl (C═O) group, serving as linker between two groups, such as forinstance hydroxyl, oxyalkyl, thioalkyl, carboxyalkyl, etc. The term“amino” as used herein alone, or as part of another group, refers to anitrogen atom that may be either terminal, or a linker between two othergroups, wherein the group may be a primary, secondary or tertiary (twohydrogen atoms bonded to the nitrogen atom, one hydrogen atom bonded tothe nitrogen atom and no hydrogen atoms bonded to the nitrogen atom,respectively) amine. The terms “sulfinyl” and “sulfonyl” as used hereinas part of another group respectively refer to an —SO— or an —SO₂—group.

To provide a more concise description, the terms ‘compound’ or‘compounds’ include tautomers, stereoisomers, N-oxides,isotopically-labelled analogues, or pharmacologically acceptable salts,also when not explicitly mentioned.

As used herein, the term “leaving group” (L) shall mean a charged oruncharged atom or group that departs during a substitution ordisplacement reaction. The term refers to groups readily displaceable bya nucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art (Smith, 2001). Examplesinclude, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides (Br, Cl, I), triflates, mesylates,tosylates, and the like.

N-oxides of the compounds mentioned above belong to the invention.Tertiary amines may or may not give rise to N-oxide metabolites. Theextent to what N-oxidation takes place varies from trace amounts to anear quantitative conversion. N-oxides may be more active than theircorresponding tertiary amines, or less active. Whilst N-oxides caneasily be reduced to their corresponding tertiary amines by chemicalmeans, in the human body this happens to varying degrees. Some N-oxidesundergo nearly quantitative reductive conversion to the correspondingtertiary amines, in other cases conversion is a mere trace reaction, oreven completely absent (Bickel, 1969).

‘Form’ is a term encompassing all solids: polymorphs, solvates,amorphous forms. ‘Crystal form’ refers to various solid forms of thesame compound, for example polymorphs, solvates and amorphous forms.‘Cocrystals’ are multicomponent crystals with a unique lattice: newchemical species produced with neutral compounds. ‘Amorphous forms’ arenon-crystalline materials with no long range order, and generally do notgive a distinctive powder X-ray diffraction pattern. Crystal forms ingeneral have been described by Byrn (1995) and Martin (1995).‘Polymorphs’ are crystal structures in which a compound can crystallizein different crystal packing arrangements, all of which have the sameelemental composition. Polymorphism is a frequently occurringphenomenon, affected by several crystallization conditions such astemperature, level of supersaturation, the presence of impurities,polarity of solvent, rate of cooling. Different polymorphs usually havedifferent X-ray diffraction patterns, solid state NMR spectra, infraredor Raman spectra, melting points, density, hardness, crystal shape,optical and electrical properties, stability, and solubility.Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

Throughout the description and the claims of this specification the word“comprise” and variations of the word, such as “comprising” and“comprises” is not intended to exclude other additives, components,integers or steps.

While it may be possible for the compounds of formula (I) to beadministered as the raw chemical, in at least one embodiment, they arepresented in a ‘pharmaceutical composition’. According to a furtheraspect, the present invention provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, together with one or more pharmaceuticallyacceptable carriers thereof, and optionally one or more othertherapeutic ingredients. The carrier(s) must be ‘acceptable’ in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof.

The term “composition” as used herein encompasses a product comprisingspecified ingredients in predetermined amounts or proportions, as wellas any product that results, directly or indirectly, from combiningspecified ingredients in specified amounts. In relation topharmaceutical compositions, this term encompasses a product comprisingone or more active ingredients, and an optional carrier comprising inertingredients, as well as any product that results, directly orindirectly, from combination, complexation or aggregation of any two ormore of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. In general, pharmaceutical compositions areprepared by uniformly and intimately bringing the active ingredient intoassociation with a liquid carrier or a finely divided solid carrier orboth, and then, if necessary, shaping the product into the desiredformulation. The pharmaceutical composition includes enough of theactive object compound to produce the desired effect upon the progressor condition of diseases. Accordingly, the pharmaceutical compositionsof the present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

Within the context of this application, the term ‘combinationpreparation’ comprises both true combinations, meaning a compound offormula (I) and other medicaments physically combined in one preparationsuch as a tablet or injection fluid, as well as ‘kit-of-parts’,comprising a compound of formula (I) and another medicament in separatedosage forms, together with instructions for use, optionally withfurther means for facilitating compliance with the administration of thecomponent compounds, e.g., label or drawings. With true combinations,the pharmacotherapy by definition is simultaneous. The contents of‘kit-of-parts’, can be administered either simultaneously or atdifferent time intervals. Therapy being either concomitant or sequentialwill be dependant on the characteristics of the other medicaments used,characteristics like onset and duration of action, plasma levels,clearance, etc., as well as on the disease, its stage, andcharacteristics of the individual patient.

The affinity of the compounds of the invention for cannabinoid CB₁receptors was determined as described below. From the binding affinitymeasured for a given compound of formula (I), one can estimate atheoretical lowest effective dose. At a concentration of the compoundequal to twice the measured K_(i)-value, nearly 100% of the cannabinoidCB₁ receptors likely will be occupied by the compound. Converting thatconcentration to mg of compound per kg of patient—assuming idealbioavailability—results in a theoretical lowest effective dose.Pharmacokinetic, pharmacodynamic, and other considerations may alter thedose actually administered to a higher or lower value. The dose of thecompound to be administered will depend on the relevant indication, theage, weight and sex of the patient and may be determined by a physician.In general, the dosage may be in amounts, for example from 0.01 mg/kg to10 mg/kg. The typical daily dose of the active ingredients varies withina wide range and will depend on various factors such as the relevantindication, the route of administration, the age, weight and sex of thepatient and may be determined by a physician. In general, total dailydose administration to a patient in single or individual doses, may bein amounts, for example, from 0.001 to 10 mg/kg body weight daily, andmore usually from 0.01 to 1,000 mg per day, of total active ingredients.Such dosages will be administered to a patient in need of treatment fromone to three times each day, or as often as needed for efficacy, and forperiods of at least two months, more typically for at least six months,or chronically.

The term “therapeutically effective amount” as used herein refers to anamount of a therapeutic agent to treat a condition treatable byadministrating a composition of the invention. That amount is the amountsufficient to exhibit a detectable therapeutic or ameliorative responsein a tissue system, animal or human. The effect may include, forexample, treating the conditions listed herein. The precise effectiveamount for a subject will depend upon the subject's size and health, thenature and extent of the condition being treated, recommendations of thetreating physician (researcher, veterinarian, medical doctor or otherclinician), and the therapeutics, or combination of therapeutics,selected for administration. Thus, it is not useful to specify an exacteffective amount in advance.

A “pharmaceutical salt” refers to an acid:base complex containing anactive pharmaceutical ingredient (API) along with additional non-toxicmolecular species in the same crystal structure. The term“pharmaceutically acceptable salt” refers to those salts that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, etc., and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell-known in the art. They can be prepared in situ when finallyisolating and purifying the compounds of the invention, or separately byreacting them with pharmaceutically acceptable non-toxic bases or acids,including inorganic or organic bases and inorganic or organic acids(Berge, 1977). Common anions used in pharmaceutically acceptable saltsinclude: chloride, bromide, sulfate, nitrate, phosphate, bicarbonate,mesylate, esylate, isothianate, tosylate, napsylate, besylate, acetate,propionate, maleate, benzoate, salicylate, fumarate, citrate, lactate,maleate, tartrate, pamoate, succinate, glycolate, hexanoate, octanoate,decanoate, stearate, oleate, aspartate and glutamate. Common cationsused as counterions in pharmaceutically acceptable salts include:sodium, potassium, calcium, magnesium, lithium, zinc, aluminum,arginine, lysine, histidine, triethylamine, ethanolamine,triethanolamine, ethilenediamine, meglumine, procaine and benzathine.

The ‘free base’ form may be regenerated by contacting the salt with abase or acid, and isolating the parent compound in the conventionalmatter. The parent form of the compound differs from the various saltforms in certain physical properties, such as solubility in polarsolvents, but otherwise the salts are equivalent to the parent form ofthe compound for the purposes of the present invention.

The term “treatment” as used herein refers to any treatment of amammalian, for example human condition or disease, and includes: (1)inhibiting the disease or condition, i.e., arresting its development,(2) relieving the disease or condition, i.e., causing the condition toregress, or (3) stopping the symptoms of the disease. The term ‘inhibit’includes its generally accepted meaning which includes restraining,alleviating, ameliorating, and slowing, stopping or reversingprogression, severity, or a resultant symptom. As used herein, the term“medical therapy” intendeds to include diagnostic and therapeuticregimens carried out in vivo or ex vivo on humans or other mammals.‘Mammals’ include animals of economic importance such as bovine, ovine,and porcine animals, especially those that produce meat, as well asdomestic animals, sports animals, zoo animals, and in at least oneembodiment humans. The term “subject” as used herein, refers to ananimal, in at least one embodiment, a mammal, for example a human, whohas been the object of treatment, observation or experiment.

EXAMPLES Example 1 Materials and Methods

¹H NMR spectra were recorded on a Varian UN400 instrument (400 MHz)using DMSO-d₆ or CDCl₃ as solvents with tetramethylsilane as an internalstandard. Chemical shifts are given in ppm (δ scale) downfield fromtetramethylsilane. Coupling constants (J) are expressed in Hz. Flashchromatography was performed using silica gel 60 (0.040-0.063 mm,Merck). Column chromatography was performed using silica gel 60(0.063-0.200 mm, Merck). Sepacore chromatographic separations werecarried out using Supelco equipment, VersaFLASH™ columns, VersaPak™silica cartridges, Büchi UV monitor C-630, Büchi Pump module C-605,Büchi fraction collector C-660 and Büchi pump manager C-615. Meltingpoints were recorded on a Büchi B-545 melting point apparatus ordetermined by DSC (differential scanning calorimetry) methods. Opticalrotations ([α]_(D)) were measured on an Optical Activity polarimeter.Specific rotations are given as deg/dm, the concentration values arereported as g/100 mL of the specified solvent and were recorded at 23°C., unless indicated otherwise.

Example 2 General Aspects of Syntheses

Pyrazoline derivatives can be obtained by published methods (Bach,1994). The synthesis of compounds having formula (I) is outlined inScheme 1. Additional information on activating and coupling methods ofamines to carboxylic acids can be found in the literature (Bodanszky,1994; Akaji, 1994; Albericio, 1997; Montalbetti, 2005).

A hydrazone derivative of general formula (II) wherein R₁ has theabovementioned meaning and R₇ is a C₁₋₃ alkyl group, such as an ethylgroup, can be obtained from a compound of general formula R₁NHNH₂ andethylglyoxalate. A hydrazone derivative of general formula (II) can bereacted with a chlorinating agent such as tert-butyl hypochlorite orN-chlorosuccinimide (NCS) in an inert solvent to give a compound ofgeneral formula (III). A compound of general formula (III) wherein R₁has the abovementioned meaning, and R₇ is a C₁₋₃ alkyl group can bereacted with a compound of general formula (IV), wherein R₂, R₅ and R₆have the abovementioned meaning, to give a compound of general formula(V) wherein R₁, R₂, R₅, R₆ and R₇ have the abovementioned meaning. Acompound of general formula (V) can be reacted with a base such asaqueous potassium hydroxide or lithium hydroxide to give a carboxylicacid derivative of general formula (VI), or a sodium, potassium, lithiumor cesium salt thereof, wherein R₁, R₂, R₅ and R₆ have theabovementioned meaning. A compound of general formula (VI) can bereacted with an amine of general formula R₃R₄NH, wherein R₃ and R₄ havethe abovementioned meaning, in the presence of an activating or couplingreagent such as 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate(CIP), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate(HBTU) in an inert organic solvent such as dichloromethane to give acompound of general formula (I) wherein R₁, R₂, R₃, R₄, R₅ and R₆ havethe abovementioned meaning. In one embodiment, a base such astriethylamine or Hünigs base (DIPEA) may be added in such reactions.

Alternatively, an ester derivative having formula (V) can be reacted ina so-called Weinreb amidation reaction with an amine of general formulaR₃R₄NH to give a compound of general formula (I). Such Weinreb amidationreactions can be promoted by the use of trimethylaluminum Al(CH₃)₃ (Formore information on aluminum-mediated conversion of esters to amides,see Levin, 1982).

Another alternative is to chlorinate a carboxylic acid derivative havingformula (VI) to the corresponding acid chloride (Va) wherein R₈ is achloro atom using a chlorinating agent such as thionyl chloride (SOCl₂)or oxalyl chloride. The formed acid chloride derivative can subsequentlybe reacted with an amine of general formula R₃R₄NH to give a compound ofgeneral formula (I), wherein R₁, R₂, R₃, R₄, R₅ and R₆ have theabovementioned meaning.

In one embodiment, the invention relates to compounds of formula (Va):

or tautomers, stereoisomers, N-oxides, isotopically-labelled analogues,or pharmacologically acceptable salts of any of the foregoing,wherein R₁, R₂, R₅ and R₆ have the abovementioned meaning and R₈ ischosen from chloro and OR₇, where R₇ is C₁₋₃ alkyl, provided that if R₂is phenyl and R₁ is benzyl, then R₇ is not ethyl. Such compounds areuseful in the synthesis of compounds of the general formula (I).

In another embodiment, the invention relates to compounds of formula(VI):

and to sodium, potassium, lithium and cesium salts thereof,wherein:

-   R₁, R₂, R₅ and R₆ have the same meanings as given above, provided    that if R₂ is phenyl, then R₁ is not benzyl. Such compounds are    useful in the synthesis of compounds of the general formula (I).

Alternatively, a compound of general formula (I) wherein R₅ and R₆ arehydrogen atoms, and R₁, R₂, R₃ and R₄ have the abovementioned meaningcan be prepared according to the route described in Scheme 2. A compoundof general formula (IX) wherein R₂ has the abovementioned meaning can beobtained from an aldehyde of general formula (VII) and a compound ofgeneral formula (VIII) in the presence of a base such as aqueouspotassium hydroxide or sodium hydroxide in a solvent such as ethanol(Annan, 1989). The formed 2-oxo-buten-3-oic acid derivative (IX) can bereacted with a compound of general formula R₃R₄NH in an inert organicsolvent such as dichloromethane in the presence of an activating orcoupling reagent such as HBTU to give an amide derivative of generalformula (X), wherein R₂, R₃ and R₄ have the abovementioned meaning. Inone embodiment, a base such as triethylamine or Hünigs base (DIPEA) maybe added in such a reaction. A compound of of general formula (X) can bereacted with a hydrazine derivative of general formula R₁NHNH₂ or itshydrate R₁NHNH₂.H₂O or a salt thereof, wherein R₁ has the abovementionedmeaning, to give a compound of general formula (I) wherein R₁, R₂, R₃and R₄ have the abovementioned meaning, and R₅ and R₆ are hydrogenatoms. A hydrazine of general formula R₁NHNH₂ (XI) can be prepared fromhydrazine or hydrazine hydrate or a salt thereof and a compound ofgeneral formula R₁-L (XII) wherein L is a ‘leaving group’ such asiodide, bromide or choride in an organic solvent such as ethanol,analogously to the method described (Chem. Ber. 1965). Alternatively, ahydrazine of general formula R₁NHNH₂ (XI) or its hydrate R₁NHNH₂.H₂O ora salt thereof, wherein R₁ has the abovementioned meaning, can beprepared from a compound of general formula R₁-L (XII) in an organicsolvent such as acetonitrile, in a reaction with a protected hydrazinederivative such as tert-butylcarbazate to give a compound of generalformula (XIII) which compound of general formula (XIII) is subsequentlyreacted with an acid such as hydrochloric acid in an inert organicsolvent such as 1,4-dioxane.

In one embodiment, the invention relates to compounds of the generalformula (X):

wherein R₂ has the same meaning as given hereinabove, R₃ is a hydrogenatom, and R₄ is chosen from C₆₋₁₀ bicycloalkyl and C₇₋₁₀ tricycloalkyl,each of which may be optionally substituted with 1-5 substituents,wherein the substituents are the same or different and are chosen frommethyl, ethyl, hydroxyl, amino, and fluoro or R₄ is chosen from2-phenyl-1,1-dimethyl-ethyl and 1-phenyl-1-methyl-ethyl, wherein thephenyl groups are optionally substituted with 1-5 substituents Y is asdefined above. Such compounds being useful in the synthesis of compoundsof the general formula (I) are new.

The selection of the particular synthetic procedures depends on factorsknown to those skilled in the art such as the compatibility offunctional groups with the reagents used, the possibility to useprotecting groups, catalysts, activating and coupling reagents and theultimate structural features present in the final compound beingprepared.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by mixing a compound ofthe present invention with a suitable acid, for instance an inorganicacid such as hydrochloric acid, or with an organic acid such as fumaricacid.

According to these procedures the compounds described below have beenprepared. They are intended to further illustrate the invention in moredetail, and therefore are not deemed to restrict the scope of theinvention in any way. Other embodiments of the invention will beapparent to those skilled in the art from consideration of thespecification and practice of the invention disclosed herein. It is thusintended that the specification and examples be considered as exemplaryonly.

Example 3 Synthesis and Spectral Data of Intermediates

To a magnetically stirred solution of oxo-acetic acid ethyl ester (35.08ml, 177 mmol; 50% solution in toluene) in ethanol (450 ml) was addedn-pentylhydrazine (21.7 g, 212 mmol) and the resulting solution washeated at 80° C. for 16 hours. The obtained mixture was allowed toattain room temperature and concentrated. The resulting residue wastaken up in ethylacetate and water. The organic layer was separated andsubsequently dried over MgSO₄, filtered and concentrated to give(pentylhydrazono)acetic acid ethyl ester (Intermediate II-1) (32.2 gram,93% yield) as a purple colored oil. ¹H-NMR (400 MHz, CDCl₃) δ 0.87-0.94(m, 3H), 1.25-1.42 (m, 7H), 1.55-1.68 (m, 2H), 3.17-3.23 (m, 1H),3.35-3.45 (m, 1H), 4.28 (q, J=7, 2H), 6.51 (br s, 1H), 6.72 (s, 1H).

Intermediate (II-2) was obtained in 94% yield analogously to thepreparation of intermediate (II-1) from oxo-acetic acid ethyl ester and4,4,4-trifluorobutylhydrazine.HCl.H₂O (Intermediate XI-3) in thepresence of 1.2 molar equivalent of Hünig's base (DIPEA). ¹H-NMR (400MHz, CDCl₃) δ 1.33 (t, J=7.1 Hz, 3H), 1.84-1.97 (m, 2H), 2.11-2.27 (m,2H), 3.33-3.40 (m, 2H), 4.28 (q, J=7.2 Hz, 2H), 6.50 (br s, 1H), 6.80(s, 1H).

To a magnetically stirred solution of (pentylhydrazono)acetic acid ethylester (Intermediate II-1) (35.16 g, 179 mmol) in ethylacetate (450 ml)was added N-chlorosuccinimide (NCS) (26.34 g, 197 mmol) and theresulting mixture was heated at 60° C. for 1 hour in a nitrogenatmosphere. To the reaction mixture was added styrene (41.1 ml, 359mmol) and potassium bicarbonate (89.8 g, 897 mmol) and water (8 ml). Theresulting mixture was heated at 70° C. for 16 hours. The resultingmixture was allowed to attain room temperature, concentrated in vacuoand the resulting residue was chromatographically separated usingSepacore equipment (eluant: dichloromethane/methanol=98/2 v/v) to giveethyl 1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate(Intermediate (V-1) (12.1 g, 22% yield) as an oil. ¹H-NMR (400 MHz,CDCl₃) δ 0.83 (t, J=7, 3H), 1.13-1.28 (m, 4H), 1.35 (t, J=7, 3H),1.53-1.67 (m, 2H), 2.89 (dd, J=16 and 13, 1H), 3.01-3.09 (m, 1H),3.14-3.22 (m, 1H), 3.41 (dd, J=16 and 12, 1H), 4.31 (double(diastereotopic) quartet, J˜7, 2H), 4.63 (dd, J=13 and 12, 1H),7.27-7.39 (m, 5H).

Intermediate (V-2) was obtained analogously to the preparation ofintermediate (V-1) from (butylhydrazono)acetic acid ethyl ester viasuccessive chlorination with N-chlorosuccinimide (NCS) and treatmentwith trans-beta-methylstyrene. Chromatographic purification usingSepacore equipment (eluant: petroleum eter (40-60)/ethylacetate=9/1v/v)) gave ethyl1-(n-butyl)-trans-4-methyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate(Intermediate (V-2) in 14% yield. ¹H-NMR (400 MHz, CDCl₃) δ 0.95 (t,J=7, 3H), 1.18-1.43 (m, 8H), 1.49-1.66 (m, 2H), 3.03-3.26 (m, 3H), 4.09(d, J=12 Hz, 1H), 4.27-4.37 (m, 2H), 7.28-7.40 (m, 5H).

Intermediate (V-3) was obtained analogously to the preparation ofintermediate (V-1) from (4,4,4-trifluorobutylhydrazono)acetic acid ethylester (Intermediate II-2) via successive reactions withN-chlorosuccinimide (NCS) and styrene to give crude intermediate (V-3).This crude material was chromatographically purified by using flashchromatography (eluant gradient: petroleum ether(40-60)/ethylacetate=95/5=>petroleum ether (40-60)/ethylacetate=93/7(v/v)) to give ethyl1-(4,4,4-trifluorobutyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate(Intermediate (V-3) (34% yield). ¹H-NMR (400 MHz, CDCl₃) δ 1.35 (t, J=7Hz, 3H), 1.75-2.22 (m, 4H), 2.93 (dd, J=18 and 14 Hz, 1H), 3.06-3.21 (m,2H), 3.41 (dd, J=18 and 12 Hz, 1H), 4.33 (double (diastereotopic)quartet, J˜7, 2H), 4.55 (dd, J=14 and 12 Hz, 1H), 7.31-7.42 (m, 5H).

To a magnetically stirred solution of ethyl1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate(Intermediate (V-1) (11.76 g, 38.74 mmol) in tetrahydrofuran (100 ml)and water (100 ml) was added lithium hydroxide (1.86 g, 77.5 mmol) andthe resulting mixture was heated at 70° C. for 1 hour. The reactionmixture was allowed to attain room temperature and diethyl ether (200ml) and concentrated hydrochloric acid (7 ml) were added. The organiclayer was separated, washed three times with water and with brine andsubsequently dried over Na₂SO₄, filtered and concentrated in vacuo togive 1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid(Intermediate (VI-1) (7.9 g, 74% yield) as an oil. ¹H-NMR (400 MHz,CDCl₃) δ 0.84 (t, J=7, 3H), 1.15-1.28 (m, 4H), 1.53-1.65 (m, 2H), 2.92(dd, J=17 and 13, 1H), 3.02-3.11 (m, 1H), 3.18-3.27 (m, 1H), 3.44 (dd,J=17 and 13, 1H), 4.75 t, J=13, 1H), 7.31-7.41 (m, 5H), 7.42-9.00 (br s,1H).

To a magnetically stirred solution of ethyl 2-fluorobenzaldehyde (11.7ml, 110 mmol) and ethylglyoxalate (11.1 ml, 100 mmol) in ethanol (50 ml)was slowly added a solution of sodium hydroxide (4.4 g (110 mmol) in 50ml water) in a nitrogen atmosphere while the temperature was keptbetween 0° C. and 10° C. After stirring for another 45 minutes thereaction mixture was allowed to attain room temperature and stirred for2 hours. The formed precipitate was collected by filtration andsuccessively washed with ethanol and a 1N HCl solution (200 ml) andsubsequently dried to give E-2-oxo-4-(2-fluorophenyl)-but-3-enoic acid(11.1 gram, 57% yield) Melting point: 100-102.5° C. ¹H-NMR (400 MHz,CDCl₃) δ 7.13-7.27 (m, 2H), 7.45-7.53 (m, 1H) 7.66-7.74 (m, 2H), 8.26(d, J=16, 1H), invisible —OH proton.

To a magnetically stirred solution of the commercially availableE-2-oxo-4-phenyl-but-3-enoic acid (4.40 gram, 25 mmol) indichloromethane (100 ml) was successively added1-(4-fluorophenyl)-1-methyl-ethylamine (3.83 g, 25 mmol),N-ethyldiisopropylamine (DIPEA) (8.56 ml, 50 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (9.48 gram, 25 mmol) and the resulting mixture was reacted atroom temperature for 16 hours in a nitrogen atmosphere. The organiclayer was washed twice with water and subsequently dried over MgSO₄,filtered and concentrated in vacuo to give crudeE-2-oxo-4-phenyl-but-3-enoic acid[1-(4-fluorophenyl)-1-methyl-ethyl]amide (Intermediate X-I) as an oil.Further chromatographic purification using Sepacore equipment (eluant:petroleum ether/ethylacetate=95/5 (v/v)) gave intermediate X-I as an oilwhich slowly solidified on standing (5.15 g, 65% yield). ¹H-NMR (400MHz, CDCl₃) δ 1.77 (s, 6H), 7.00-7.05 (m, 2H), 7.35-7.45 (m, 5H), 7.52(br s, 1H), 7.61-7.65 (m, 2H), 7.73 (d, J=16, 1H), 7.92 (d, J=16, 1H).

Intermediate X-2 (E-2-oxo-4-phenyl-but-3-enoic acid[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo-[2.2.1]hept-2-ylamide]) wasobtained from E-2-oxo-4-phenyl-but-3-enoic acid andendo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamine (CAS32511-34-5) analogously to the procedure described for intermediate X-1.¹H-NMR (400 MHz, CDCl₃) δ 0.84-1.00 (m, 10H), 1.21-1.29 (m, 1H),1.38-1.48 (m, 1H), 1.53-1.62 (m, 1H), 1.70-1.86 (m, 2H), 2.33-2.44 (m,1H), 4.22-4.30 (m, 1H), 7.20-7.26 (m, 1H), 7.39-7.46 (m, 3H), 7.65-7.70(m, 2H), 7.78 (d, J=16, 1H), 7.95 (d, J=16, 1H).

Intermediate X-3 (E-2-oxo-4-(2-fluorophenyl)-but-3-enoic acid[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamide]) wasobtained from E-2-oxo-4-(2-fluorophenyl)-but-3-enoic acid (IntermediateIX-1) and endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamineanalogously to the procedure described for intermediate X-1. ¹H-NMR (400MHz, CDCl₃) δ 0.84-1.00 (m, 10H), 1.21-1.30 (m, 1H), 1.38-1.48 (m, 1H),1.53-1.62 (m, 1H), 1.70-1.87 (m, 2H), 2.34-2.44 (m, 1H), 4.21-4.30 (m,1H), 7.10-7.25 (m, 3H), 7.38-7.45 (m, 1H), 7.70-7.75 (m, 1H), 7.85 (d,J=16, 1H), 8.12 (d, J=16, 1H).

Intermediate X-4 (E-2-oxo-4-phenyl-but-3-enoic acid[2-(4-fluorophenyl)-2,2-dimethyl-ethyl]amide was obtained fromE-2-oxo-4-phenyl-but-3-enoic acid and2-(4-fluorophenyl)-2,2-dimethyl-ethylamine analogously to the proceduredescribed for intermediate X-1. ¹H-NMR (400 MHz, CDCl₃) δ 1.40 (s, 6H),3.08 (s, 2H), 6.91-6.99 (m, 3H), 7.06-7.11 (m, 2H), 7.38-7.47 (m, 3H),7.65-7.70 (m, 2H), 7.82 (d, J=16, 1H), 7.92 (d, J=16, 1H).

Intermediate X-5 (E-2-oxo-4-(4-chlorophenyl)-but-3-enoic acid[1-phenyl-1-methyl-ethyl]amide was obtained fromE-2-oxo-4-(4-chlorophenyl)-but-3-enoic acid and1-phenyl-1-methyl-ethylamine analogously to the procedure described forintermediate X-1. ¹H-NMR (400 MHz, CDCl₃) δ 1.79 (s, 6H), 7.23-7.28 (m,1H), 7.32-7.43 (m, 6H), 7.51-7.57 (m, 3H), 7.71 (d, J=16 Hz, 1H), 7.85(d, J=16 Hz, 1H).

Intermediate X-6 (E-2-oxo-4-(3-methoxyphenyl)-but-3-enoic acid[1-(4-fluorophenyl)-1-methyl-ethyl]amide was obtained fromE-2-oxo-4-(3-methoxyphenyl)-but-3-enoic acid and1-(4-fluorophenyl)-1-methyl-ethylamine analogously to the proceduredescribed for intermediate X-1. ¹H-NMR (400 MHz, CDCl₃) δ 1.77 (s, 6H),3.81 (s, 3H), 6.95-7.05 (m, 3H), 7.13-7.16 (m, 1H), 7.18-7.22 (m, 1H),7.28-7.33 (m, 1H), 7.36-7.40 (m, 2H), 7.54 (br s, 1H), 7.71 (d, J=16 Hz,1H), 7.88 (d, J=16 Hz, 1H).

To a magnetically stirred solution of hydrazine hydrate (243 ml, 5 mol)was very slowly added a solution of 1-bromopentane (62 ml, 0.50 mol) inethanol (50 ml) while keeping the temperature at 20° C. The resultingmixture was reacted at room temperature for 2 hours. The mixture wasextracted with diethyl ether. The diethyl ether extract was concentratedand BaO (5 gram) was added to the residue. Distillation in vacuo gaven-pentylhydrazine (Intermediate XI-1) at 30-40 mbar pressure at 72°C.-78° C. (30.36 gram, 48% yield). ¹H-NMR (400 MHz, CDCl₃) δ 0.90 (t,J=7, 3H), 1.27-1.38 (m, 4H), 1.45-1.58 (m, 2H), 2.76 (t, J=7, 2H), 2.85(br s, 3H).

Step A: To a magnetically stirred solution of tert-butylcarbazate (47.5gram, 359 mmol) in anhydrous acetonitrile (300 ml) was successivelyadded DIPEA (Hünig's base) (37.6 ml, 216 mmol) and 1-bromobutane (19.3ml, 180 mmol). The resulting mixture was reacted at 60° C. for 16 hours.The resulting mixture was allowed to attain room temperature andsubsequently concentrated in vacuo and further purified by Sepacorechromatography (eluant: petroleum ether 40-60/ethylacetate=4/1 (v/v)) togive N′-butylhydrazine-carboxylic acid tert-butyl ester (intermediateXIII-1) (13.2 gram, 39%) as a pale yellow oil: ¹H-NMR (400 MHz, CDCl₃) δ0.91 (t, J=7, 3H), 1.30-1.49 (m, 13H), 2.81-2.87 (m, 2H), 4.00 (br s,1H), 6.20 (br s, 1H).

Step B: To a magnetically stirred solution ofN′-butylhydrazine-carboxylic acid tert-butyl ester (intermediate XIII-1)(13.17 gram, 70 mmol) in 1,4-dioxane (100 ml) was added excess (12 molequivalents) hydrochloric acid (12 N) and the resulting mixture wasreacted for 16 hours at room temperature. The resulting mixture wasconcentrated in vacuo and triturated with diethyl ether to given-butylhydrazine.HCl.H₂O (Intermediate XI-2) (9.63 gram, 92% yield).¹H-NMR (400 MHz, DMSO-d₆/CDCl₃=4/1 (v/v)) δ 0.93 (t, J=7, 3H), 1.32-1.43(m, 2H), 1.56-1.65 (m, 2H), 2.92-2.98 (m, 2H), 7.20 (br s, ˜6H).

Step A: Intermediate (XI-3) was obtained analogously to the proceduredescribed for intermediate (XI-2) from tert-butylcarbazate and1-bromo-4,4,4-trifluorobutane viaN′-(4,4,4-trifluorobutyl)hydrazine-carboxylic acid tert-butyl ester(intermediate XIII-2): Intermediate XIII-2: ¹H-NMR (400 MHz, CDCl₃) δ1.46 (s, 9H), 1.67-1.76 (m, 2H), 2.10-2.24 (m, 2H), 2.87-2.94 (m, 2H),3.97 (br s, 1H), 6.05 (br s, 1H).

Step B: N′-(4,4,4-trifluorobutyl)hydrazine-carboxylic acid tert-butylester (intermediate XIII-2) was converted with excess hydrochloric acidto intermediate (XI-3) (4,4,4-trifluorobutylhydrazine.HCl.H₂O)analogously as described for the preparation of intermediate XI-2 (partB). Intermediate (XI-3): ¹H-NMR (400 MHz, DMSO-d₆ δ 1.77 (quintet, J=7.7Hz, 2H), 2.28-2.43 (m, 2H), 2.94 (t, J=7.4 Hz, 2H), 7.95 (br s, ˜3H).

Example 4 Synthesis of Specific Compounds

N-(Adamant-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

To a magnetically stirred solution of1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid(Intermediate (VI-1) (0.70 g, 2.55 mmol) in dichloromethane (40 ml) wassuccessively added 2-adamantanamine.HCl (480 mg, 2.55 mmol),N-ethyldiisopropylamine (DIPEA) (1.78 ml, 10.22 mmol) and2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP) (853 mg,3.07 mol) and the resulting mixture was reacted at room temperature for16 hours in a nitrogen atmosphere. The reaction mixture was successivelywashed twice with water, twice with aqueous citric acid (0.5 M), twicewith NaHCO₃ (5% aqueous solution) and brine, and subsequently dried overNa₂SO₄, filtered and concentrated in vacuo to give crudeN-(adamant-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(1.26 g) as an orange oil. Further chromatographic purification usingSepacore equipment (eluant: petroleum ether/diethyl ether=85/15 (v/v))gave compound 1 (750 mg, 67% yield) as an oil. ¹H-NMR (400 MHz, CDCl₃) δ0.85 (t, J=7, 3H), 1.21-1.30 (m, 4H), 1.55-1.65 (m, 2H), 1.65-1.70 (m,2H), 1.76 (br s, 2H), 1.75-1.92 (m, 8H), 1.97-2.01 (m, 2H), 2.82 (dd,J=17 and 14, 1H), 2.92-2.97 (m, 2H), 3.42 (dd, J=17 and 11, 1H),4.09-4.14 (m, 1H), 4.40 (dd, J=14 and 11, 1H), 6.99-7.07 (m, 1H),7.28-7.38 (m, 5H).

Compounds 2-100 were analogously prepared.

N-Phenyl-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7 Hz, 3H), 1.17-1.34 (m, 4H),1.55-1.73 (m, 2H), 2.85-3.08 (m, 3H), 3.49 (dd, J=17 and 11.4 Hz, 1H),4.53 (dd, J=14 and 11.4 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 7.28-7.42 (m,7H), 7.62 (d, J=7.5 Hz, 2H), 8.43 (s, 1H).

N-(4-Methoxyphenyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=6.9 Hz, 3H), 1.19-1.34 (m, 4H)1.57-1.69 (m, 2H), 2.85-3.06 (m, 3H), 3.48 (dd, J=17 and 11 Hz, 1H),3.80 (s, 3H), 4.50 (dd, J=14 and 11.4 Hz, 1H), 6.88 (d, J=9 Hz, 2H),7.28-7.40 (m, 5H) 7.54 (d, J=9 Hz, 2H), 8.35 (br s, 1 H).

N-(Napht-1-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7 Hz, 3H), 1.20-1.40 (m, 4H),1.66-1.77 (m, 2H), 2.92-3.14 (m, 3H), 3.55 (dd, J=17 and 11.4 Hz, 1 H),4.59 (dd, J=14 and 11.4 Hz, 1H), 7.30-7.44 (m, 5H), 7.46-7.61 (m, 3H),7.67 (d, J=8.4 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H),8.20 (d, J=7.5 Hz, 1H), 9.05 (br s, 1H).

N-(2-Trifluoromethyl)phenyl-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.2 Hz, 3H), 1.18-1.38 (m, 4H),1.61-1.70 (m, 2H), 2.86-3.11 (m, 3H), 3.49 (dd, J=17 and 11.7 Hz, 1H),4.59 (dd, J=14 and 11.4 Hz, 1H), 7.17 (t, J=7.7 Hz, 1H), 7.29-7.42 (m,5H), 7.55 (t, J=7.8 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 8.45 (d, J=8.4 Hz,1H), 9.05 (br s, 1H).

N-(Naphthalen-1-ylmethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.79 (t, J=6.9 Hz, 3H), 1.07-1.25 (m, 4H),1.44-1.58 (m, 2H), 2.78-2.92 (m, 3H), 3.46 (dd, J=17.3, and 11.3 Hz,1H), 4.41 (dd, J=14.3 and 11.3 Hz, 1H), 5.00 (d, J=5.7 Hz, 2H), 6.90 (brt, J=5.6 Hz, 1H), 7.27-7.37 (m, 5H), 7.42-7.60 (m, 4H), 7.83 (d, J=7.8Hz, 1H), 7.88 (d, J=1.2 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H).

N-(Pyridin-3-ylmethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.83 (t, J=6.9 Hz, 3H), 1.14-1.30 (m, 4H),1.51-1.64 (m, 2H), 2.81-2.99 (m, 3H), 3.44 (dd, J=17.3 and 11.3 Hz, 1H),4.45 (dd, J=14.30 and 11.29 Hz, 1H), 4.56 (d, J=6.3 Hz, 2H), 7.00 (br t,J=5.9 Hz, 1H), 7.26-7.39 (m, 6H), 7.70 (br d, J=7.8 Hz, 1H), 8.54 (dd,J=4.8 and 1.50 Hz, 1H), 8.60 (d, 1H).

N-(Cyclohexylmethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.9 Hz, 3H), 0.90-1.04 (m, 2H),1.12-1.33 (m, 7H), 1.47-1.82 (m, 8H), 2.76-2.98 (m, 3H), 3.18 (dq,J=12.9 and 6.6 Hz, 2H), 3.41 (dd, J=17.3 and 11 Hz, 1H), 4.39 (dd,J=14.3 and 11 Hz, 1H), 6.68 (br t, J=5.9 Hz, 1H), 7.27-7.41 (m, 5H).

N-(2,2-diphenylethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.83 (t, J=7.07 Hz, 3H), 1.09-1.28 (m, 4H),1.43-1.58 m, 2H), 2.73-2.91 (m, 3H), 3.37 (dd, J=17.2 and 11.1 Hz, 1H),3.98 (dd, J=7.8 and 6.2 Hz, 2H), 4.26 (t, J=7.8 Hz, 1H), 4.36 (dd,J=14.3 and 11.3 Hz, 1H), 6.62 (br t, J=5.9 Hz, 1H), 7.18-7.37 (m, 15H).

N-(Benzyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.83 (t, J=6.9 Hz, 3H), 1.13-1.29 (m, 4H),1.49-1.64 (m, 2H), 2.81-2.96 (m, 3H), 3.44 (dd, J=17.3 and 11.3 Hz, 1H),4.42 (dd, J=14.5 and 11.1 Hz, 1H), 4.54 (d, J=6 Hz, 2H), 6.94 (br t,J=5.7 Hz, 1H), 7.26-7.40 (m, 10H).

N-[(1-Ethyl)propyl]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.9 Hz, 3H), 0.94 (t, J=7, 6H),1.17-1.31 (m, 4H), 1.39-1.52 (m, 2H), 1.53-1.69 (m, 4H), 2.78-2.98 (m,3H), 3.42 (dd, J=17.3 and 11 Hz, 1H), 3.79-3.90 (m, 1H), 4.40 (dd,J=14.4 and 11.1 Hz, 1H), 6.35 (d, J=9.3 Hz, 1H), 7.27-7.40 (m, 5H).

N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (d, J=6.9 Hz, 3H), 1.10-1.65 (m, 13H),1.83 (ddd, J=13.1 and 8 and 2.1 Hz, 1H), 2.25-2.34 (m, 2H), 2.76-2.97(m, 3H), 3.40-3.41 (2x dd, J=18.4 and 11.1 Hz, 1H), 3.79 (br td, J=7.7and 3.6 Hz, 1H), 4.37-4.38 (2x dd, J=14.4 and 11.1 and 3.3 Hz, 1H), 6.46(br d, J=7.2 Hz, 1H), 7.27-7.40 (m, 5H).

N-[2-(4-Fluorophenyl)ethyl]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.9 Hz, 3H), 1.15-1.31 (m, 4H),1.51-1.65 (m, 2H), 2.78-2.97 (m, 5H), 3.41 (dd, J=17.1 and 11.1 Hz, 1H),3.52-3.60 (m, 2H), 4.41 (dd, J=14.3 and 11.3 Hz, 1H), 6.69 (br t, J=5.9Hz, 1H), 7.00 (br t, J=8.7 Hz, 2H), 7.19 (dd, J=8.4 and 5.4 Hz, 2H),7.27-7.40 (m, 5H).

N-(1-Phenyl-ethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(1:1 diastereomeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.84 (t, J=6.5 Hz, 3H), 1.15-1.30 (m, 4H),1.48-1.67 (m, 5H), 2.76-2.96 (m, 3H), 3.39-3.40 (2 x dd, J=17.4 and11.1, 1H), 4.39-4.40 (2 x dd, J=14.3 and 11.1 Hz, 1H), 5.14-5.25 (m,1H), 6.86 (br d, J=8.1 Hz, 1H), 7.26-7.41 (m, 10H).

N-(Adamantylmethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.9 Hz, 3H), 1.18-1.32 (m, 4H),1.49-1.78 (m, 14H), 2.00 (br s, 3H), 2.78-3.11 (m, 5H), 3.42 (dd, J=17.1and 11.1 Hz, 1H), 4.40 (dd, J=14.4 and 11.1 Hz, 1H), 6.69 (br t, J=6.3Hz, 1H), 7.26-7.40 (m, 5H).

N-[(1-Ethyl)propyl]-1-(n-butyl)-5-(3-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.4 Hz, 3H), 0.94 (t, J=7.4 Hz,6H), 1.19-1.70 (m, 8H), 2.79 (dd, J=17.3 and 14.3 Hz, 1H), 2.89-2.95 (m,2H), 3.43 (dd, J=17.4 and 11.1 Hz, 1H), 3.79-3.90 (m, 1H), 4.36 (dd,J=14.4 and 11.1 Hz, 1H), 6.33 (br d, J=9.3 Hz, 1H), 7.23-7.36 (m, 3H),7.38 (br s, 1H).

N-(Cyclooctyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.92 Hz, 3H), 1.16-1.31 (m, 4H),1.48-1.75 (m, 14H), 1.82-1.94 (m, 2H), 2.76-2.97 (m, 3H), 3.40 (dd,J=17.4 and 11.1 Hz, 1H), 4.00-4.10 (m, 1H), 4.37 (dd, J=14.3 and 11 Hz,1H), 6.58 (br d, J=8.4 Hz, 1H), 7.27-7.39 (m, 5H).

N-(2,2-diphenylpropyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7.1 Hz, 3H), 1.10-1.28 (m, 4H),1.44-1.55 (m, 2H), 1.71 (s, 3H), 2.71-2.87 (m, 3H), 3.37 (dd, J=17.1 and11.1 Hz, 1H), 4.02 (d, J=6.3 Hz, 2H), 4.34 (dd, J=14.4 and 11.1 Hz, 1H),6.41 (br t, J=5.87 Hz, 1H), 7.19-7.37 (m, 15H).

N-(Cycloheptyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.9 Hz, 3H), 1.15-1.31 (m, 4H),1.45-1.72 (m, 12H), 1.91-2.03 (m, 2H), 2.76-2.97 (m, 3H), 3.40 (dd,J=17.1 and 11.1 Hz, 1H), 3.95-4.08 (m, 1H), 4.38 (dd, J=14.3 and 11 Hz,1H), 6.57 (br d, J=8.4 Hz, 1H), 7.27-7.40 (m, 5H).

N-(Quinolin-3-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.88 (t, J=6.92 Hz, 3H), 1.18-1.36 (m, 4H),1.58-1.71 (m, 2H), 2.91-3.14 (m, 3H), 3.53 (dd, J=17.3 and 11.6 Hz, 1H),4.62 (dd, J=13.8 and 11.7 Hz, 1H), 7.29-7.45 (m, 5H), 7.53 (br t, J=6.9Hz, 1H), 7.62 (dt, J=7.7 and 1.50 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 8.05(d, J=8.4 Hz, 1H), 8.69 (s, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.86 (d, J=2.7Hz, 1H).

N-(2-phenyl-trans-cyclopropyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.92 Hz, 3H), 1.15-1.33 (m, 6H),1.52-1.68 (m, 2H), 2.11-2.19 (m, 1H), 2.76-2.98 (m, 4H), 3.41 and 3.43(2x dd, J=17.2 and 11.2 Hz, 1H), 4.42 (dd, J=14.1 and 11.1 Hz, 1H), 6.84(br s, 1H), 7.15-7.39 (m, 10H).

N-[3-(Trifluoromethyl)benzyl)]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.83 (t, J=6.92 Hz, 3H), 1.15-1.30 (m, 4H),1.51-1.65 (m, 2H), 2.81-2.99 (m, 3H), 3.45 (dd, J=17.3 and 11.3 Hz, 1H),4.46 (dd, J=14.4 and 11.4 Hz, 1H), 4.59 (s, 2H), 7.28-7.39 (m, 5H),7.43-7.50 (m, 1H), 7.52-7.60 (m, 3H).

N-(2,2-Dimethylpropyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7.22 Hz, 3H), 0.96 (s, 9H),1.16-1.32 (m, 4H), 1.53-1.67 (m, 2H), 2.77-2.97 (m, 3H), 3.15 (dd, J=6.6and 1.8 Hz, 2H), 3.42 (dd, J=17.5 and 11.1 Hz, 1H), 4.41 (dd, J=14.4 and11.1 Hz, 1H), 6.72 (br t, J=6.2 Hz, 1H), 7.27-7.40 (m, 5H).

N-(2-Indanyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.82 (t, J=6.9 Hz, 3H), 1.11-1.29 (m, 4H),1.47-1.64 (m, 2H), 2.77-2.96 (m, 4H), 3.32-3.47 (m, 3H), 4.40 (dd,J=14.3 and 11.3 Hz, 1H), 4.76-4.87 (m, 1H), 6.80 (br d, J=7.8 Hz, 1H),7.14-7.40 (m, 10H).

N-[(1R,2S,5R)-rel-6,6-dimethylbicyclo[3.1.1.]heptan-2-methyl]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture) (from (−)-cis-myrtanylamine (CAS 38235-68-6))

¹H-NMR (400 MHz, CDCl₃) δ 0.80-0.90 (m, 3H), 0.91 (d, J=9.6 Hz, 1H),1.07 (s, 3H), 1.17-1.32 (m, 7H), 1.47-1.67 (m, 3H), 1.81-2.04 (m, 5H),2.27-2.42 (m, 2H), 2.77-2.98 (m, 3H), 3.27-3.49 (m, 3H), 4.39 (dd,J=14.4 and 11.1 Hz, 1H), 6.64 (br t, J=5.7 Hz, 1H), 7.27-7.39 (m, 5H).

N-[(3-Dimethylamino)-2,2-dimethylpropyl]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.92 Hz, 3H), 0.94 (s, 3H), 0.95(s, 3H), 1.17-1.34 (m, 4H), 1.58-1.70 (m, 2H), 2.26 (s, 2H), 2.33 (s,6H), 2.78-2.94 (m, 3H), 3.24 (d, J=5.4 Hz, 2H), 3.40 (dd, J=17.1 and10.8 Hz, 1H), 4.35 (dd, J=14.6 and 11 Hz, 1H), 7.28-7.41 (m, 5H), 8.58(br s, 1H).

N-(Adamantyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.84 (t, J=6.92 Hz, 3H), 1.15-1.32 (m, 4H)1.49-1.64 (m, 2H), 1.65-1.76 (m, 7H), 2.08 (br s, 8H), 2.78 (dd, J=17.1and 14.4 Hz, 1H), 2.89 (t, J=7.5 Hz, 2H), 3.37 (dd, J=17.3 and 11 Hz,1H) 4.35 (dd, J=14.6 and 11 Hz, 1H), 6.40 (br s, 1H), 7.27-7.41 (m, 5H).

N-(1-Phenyl-1-methyl-ethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.9 Hz, 3H), 1.16-1.33 (m, 4H),1.51-1.69 (m, 2H), 1.75 (s, 3H), 1.77 (s, 3H), 2.78 (dd, J=17.3 and 14.6Hz, 1H), 2.92 (br t, J=7.1 Hz, 2H), 3.35 (dd, J=17.3 and 11 Hz, 1H),4.38 (dd, J=14.4 and 11.1 Hz, 1H), 6.97 (br s, 1H), 7.19-7.24 (m, 1H),7.27-7.41 (m, 7H), 7.45 (br d, J=7.2 Hz, 2H).

N-(N,2,2,6,6-pentamethylpiperidin-4-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7.1 Hz, 3H), 1.10 (s, 6H). 1.16 (s,6H). 1.19-1.30 (m, 4H). 1.37 (br t, J=11.4 Hz, 2H), 1.50-1.68 (m, 2H),1.86 (dd, J=12.3 and 3.3 Hz, 2H), 2.26 (s, 3H), 2.81 (dd, J=17.5 and14.4 Hz, 1H), 2.86-2.97 (m, 2H), 3.40 (dd, J=17.1 and 11.1 Hz, 1H),4.14-4.30 (m, 1H), 4.39 (dd, J=14.4 and 11.1 Hz, 1H), 6.39 (br d, J=8.1Hz, 1H), 7.27-7.40 (m, 5H).

N-Methyl-N-(Naphthalen-1-yl-methyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) (broad signals due to restricted amide bondrotation) δ 0.56-1.78 (m, 9H), 2.48-3.08 (m, 3H), 3.10 (br s) and 3.26(br s: Together integrates for 3H), 3.40-3.59 (m, 1H), 4.15-4.40 (m,1H), 5.18 (br s) and 5.50 (br d, J=16 Hz) and 5.64 (br d, J=16 Hz;Together integrates for 2H), 7.26-7.58 (m, 9H), 7.80 (br s, 1H), 7.88(br d, J=7 Hz, 1H), 7.92-8.17 (m, 1H),

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-(pyrid-2-yl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, DMSO-d₆) δ 0.81-0.95 (m, 10H), 0.97 (s, 3H), 1.16-1.35(m, 4H), 1.35-1.66 (m, 5H), 1.69 (t, J=4.4 Hz, 1H), 1.74-1.87 (m, 1H),2.32-2.44 (m, 1H), 2.91-3.11 (m, 3H), 3.44-3.59 (m, 1H), 4.24-4.35 (m,1H), 4.54-4.67 (m, 1H), 6.69 (br d, J=8.4 Hz, 1H), 7.20-7.27 (m, 1H),7.46 (dd, J=7.8 and 4.5 Hz, 1H), 7.72 (br t, J=7.5 Hz, 1H), 8.58 (br t,J=4 Hz, 1H).

N-(1-Phenyl-1-methyl-ethyl)-1-(n-pentyl)-5-(pyrid-2-yl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, DMSO-d₆) δ 0.84 (t, J=6.9 Hz, 3H), 1.17-1.31 (m, 4H),1.52-1.65 (m, 2H), 1.73 (s, 3H), 1.75 (s, 3H), 2.88-3.10 (m, 3H), 3.40(dd, J=17.3 and 11.6 Hz, 1H), 4.59 (dd, J=13.67 and 11.6 Hz, 1H), 7.02(br s, 1H), 7.19-7.28 (m, 2H), 7.33 (br t, J=7.7 Hz, 2H), 7.40-7.48 (m,3H), 7.74 (dt, J=7.7 and 1.8 Hz, 1H), 8.57 (br d, J=3.9 Hz, 1H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5-(3-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 1)

Compounds 33 and 34 were separated from the corresponding diastereomericmixture by flash chromatography (silicagel). Eluant: petroleum ether(40-60)/diethyl ether=4/1 v/v).

¹H-NMR (400 MHz, CDCl₃) δ 0.81-0.95 (m, 10H), 0.97 (s, 3H), 1.20-1.48(m, 4H), 1.52-1.63 (m, 3H), 1.69 (t, J=4.5 Hz, 1H), 1.74-1.86 (m, 1H),2.32-2.43 (m, 1H), 2.78 (dd, J=17.4 and 14.1 Hz, 1H), 2.95 (t, J=7.4 Hz,2H), 3.38-3.48 (m, 1H) 4.25-4.34 (m, 1H), 4.38 (dd, J=14.1 and 11.4 Hz,1H), 6.66 (br d, J=9.3 Hz, 1H), 7.20-7.39 (m, 4H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5-(3-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 2)

¹H-NMR (400 MHz, CDCl₃) δ 0.82-0.95 (m, 10H), 0.97 (s, 3H), 1.21-1.47(m, 4H) 1.51-1.65 (m, 3H), 1.69 (t, J=4.3 Hz, 1H), 1.75-1.86 (m, 1H),2.33-2.43 (m, 1H), 2.79 (dd, J=17.3 and 14.3 Hz, 1H), 2.94 (t, J=7.2 Hz,2H), 3.42 (dd, J=17.4 and 11.1 Hz, 1H), 4.26-4.41 (m, 2H), 6.65 (d, J=9Hz, 1H), 7.23-7.31 (m, 3H), 7.39 (br s, 1H).

N-(1-Phenyl-1-methyl-ethyl)-1-(n-butyl)-5-(3-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.4 Hz, 3H), 1.21-1.43 (m, 2H),1.54-1.64 (m, 2H), 1.75 (s, 3H), 1.77 (s, 3H), 2.74 (dd, J=17.4 and 14.1Hz, 1 H), 2.93 (t, J=7.3 Hz, 2H), 3.36 (dd, J=17.1 and 11.1 Hz, 1H),4.35 (dd, J=14.3 and 11.3 Hz, 1H), 6.96 (br s, 1H), 7.21-7.30 (m, 4H),7.31-7.38 (m, 3H), 7.45 (br d, J=8.1 Hz, 2H).

N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-(n-butyl)-5-(3-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.4 Hz, 3H), 1.21-1.41 (m, 2H),1.54-1.64 (m, 2H), 1.74 (s, 3H), 1.75 (s, 3H), 2.73 (dd, J=17.4 and 14.4Hz, 1H), 2.93 (t, J=7.4 Hz, 2H), 3.35 (dd, J=17.3 and 11.3 Hz, 1H), 4.35(dd, J=14.1 and 11.1 Hz, 1H), 6.93 (br s, 1H), 7.01 (br t, J=8.7 Hz,2H), 7.21-7.31 (m, 3H), 7.36-7.44 (m, 3H).

N-(1-Phenyl-1-methyl-ethyl)-1-(n-butyl)-trans-4-methyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

A Sepacore chromatographic purification was applied to purify the crudecompound 37: Eluant: Dichloromethane.

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7.4 Hz, 3H), 1.19-1.38 (m, 5H),1.51-1.61 (m, 2H), 1.74 (s, 3H), 1.77 (s, 3H), 2.89-2.97 (m, 2H), 3.14(dq, J=13.4 and 6.7 Hz, 1H), 3.84 (d, J=13.2 Hz, 1H), 6.98 (br s, 1H),7.23 (br t, J=7.4 Hz, 1H), 7.28-7.39 (m, 7H), 7.45 (br d, J=7.2 Hz, 2H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-trans-4-methyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

Two successive Sepacore chromatographic purifications were applied toisolate compound 38 from the crude reaction mixture: Separation A:Eluant: petroleum ether (40-60)/diethyl ether=80/20. Separation B:Eluant: petroleum ether (40-60)/ethylacetate=90/10.

¹H-NMR (400 MHz, CDCl₃) δ 0.81-0.94 (m, 10H), 0.97 (s, 3H) 1.21-1.47 (m,6H), 1.50-1.67 (m, 4H), 1.69 (t, J=4.5 Hz, 1H), 1.74-1.86 (m, 1H),2.32-2.44 (m, 1H), 2.88-3.02 (m, 2H), 3.13-3.25 (m, 1H), 3.81-3.90 (m,1H), 4.22-4.36 (m, 1H), 6.64-6.73 (m, 1H), 7.29-7.41 (m, 5H).

N-(Endo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7.1 Hz, 3H), 1.16-1.38 (m, 7H),1.40-1.68 (m, 6H), 2.06-2.17 (m, 1H), 2.24 (br s, 1H), 2.49 (br s, 1H),2.82 (dd, J=16.5 and 14.4 Hz, 1H), 2.88-3.01 (m, 2H), 3.41 (dd, J=17.1and 11.1 Hz, 1H), 4.13-4.24 (m, 1H), 4.35-4.47 (m, 1H), 6.60-6.73 (m,1H), 7.28-7.43 (m, 5H).

Compound 12 was separated by preparative chiral HPLC into 4 separatestereoisomers (compounds 40, 41, 42 and 43, respectively).

N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(compound 40) (stereoisomer 1; first eluting diastereomer; retentiontime=10.29 minutes; Diastereomeric excess=97%): [α²⁵ _(D)]=+147°, c=0.9,methanol.

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7 Hz, 3H), 1.10-1.66 (m, 15H), 1.83(ddd, J=13, 8 and 2.1 Hz, 1H), 2.25-2.33 (m, 2H), 2.81 (dd, J=17.3 and14.3 Hz, 1H), 2.86-2.97 (m, 2H), 3.40 (dd, J=17.4 and 11.1 Hz, 1H), 3.79(br td, J=7.6 and 3.4 Hz, 1H), 4.37 (dd, J=14.30 and 11 Hz, 1H), 6.45(br d, J=7.5 Hz, 1H), 7.27-7.40 (m, 5H).

N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(compound 41) (stereoisomer 2; second eluting diastereomer; retentiontime=12.57 minutes; Diastereomeric excess >99%): [α²⁵ _(D)]=+158°,c=1.1, methanol.

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7 Hz, 3H), 1.11-1.65 (m, 15H), 1.83(ddd, J=13, 8 and 2.1 Hz, 1H), 2.26-2.33 (m, 2H), 2.81 (dd, J=17.3 and14.3 Hz, 1H), 2.86-2.98 (m, 2H), 3.40 (dd, J=17.4 and 11.1 Hz, 1H), 3.79(br td, J=7.6 and 3.4 Hz, 1H), 4.38 (dd, J=14.4 and 11.1 Hz, 1H), 6.45(br d, J=7.2 Hz, 1H), 7.27-7.38 (m, 5H).

N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(compound 42) (stereoisomer 3; third eluting diastereomer; retentiontime=13.71 minutes; Diastereomeric excess >99%): [α²⁵ _(D)]=−173°,c=1.0, methanol.

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7 Hz, 3H), 1.10-1.66 (m, 15H), 1.83(ddd, J=13, 8 and 2.1 Hz, 1H), 2.24-2.34 (m, 2H), 2.81 (dd, J=17.3 and14.3 Hz, 1H), 2.86-2.98 (m, 2H), 3.40 (dd, J=17.4 and 11.1 Hz, 1H), 3.79(br td, J=7.6 and 3.4 Hz, 1H), 4.38 (dd, J=14.2 and 11.1 Hz, 1H), 6.45(br d, J=7.5 Hz, 1H), 7.27-7.37 (m, 5H).

N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(compound 43) (stereoisomer 4; fourth eluting diastereomer; retentiontime=23.01 minutes; Diastereomeric excess >99%): [α²⁵ _(D)]=−162°,c=0.9, methanol.

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7 Hz, 3H), 1.10-1.66 (m, 15H), 1.83(ddd, J=12.9, 8.1 and 2.1 Hz, 1H), 2.25-2.34 (m, 2H), 2.81 (dd, J=17.2and 14.4 Hz, 1H), 2.85-2.98 (m, 2H), 3.40 (dd, J=17.2 and 11.1 Hz, 1H),3.79 (br td, J=7.6 and 3.6 Hz, 1H), 4.37 (dd, J=14.2 and 11.1 Hz, 1H),6.45 (br d, J=7.2 Hz, 1H), 7.27-7.40 (m, 5H).

Preparative chiral HPLC method: First step: A 250×30 mm column was used.Stationary phase: CHIRALPAK® AD=H 5 μm. n-Heptane/isopropanol=95/05(v/v) was used as the mobile phase. Flow rate: 40 ml/minute.Temperature: 21.5° C. Detection UV 325 nm. Second step: A 250×30 mmcolumn was used. Stationary phase: CHIRALPAK® IA 5 μm.n-Heptane/ethylacetate=85/15 (v/v) was used as the mobile phase. Flowrate: 40 ml/minute. Temperature: ambient. Detection UV 325 nm.

Analytical HPLC monitoring system: A 250×4.6 mm column was used.Stationary phase: CHIRALPAK® IA-H 5 μm. n-Heptane/ethylacetate=80/20(v/v) was used as the mobile phase. Flow rate: 1 ml/minute. Temperature:25° C. Detection: UV 300 nm.

Racemic compound 22 (1.88 gram) was separated by preparative chiral HPLCinto 2 separate enantiomers (compounds 44 and 45, respectively).

(+)-N-[3-(Trifluoromethyl)benzyl)]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(compound 44)

[α²⁵ _(D)]=124°, c=1.0, methanol. ¹H-NMR (400 MHz, CDCl₃) δ 0.83 (t,J=6.92 Hz, 3H), 1.15-1.30 (m, 4H), 1.51-1.65 (m, 2H), 2.81-2.99 (m, 3H),3.45 (dd, J=17.3 and 11.3 Hz, 1H), 4.46 (dd, J=14.4 and 11.4 Hz, 1H),4.59 (s, 2H), 7.28-7.39 (m, 5H), 7.43-7.50 (m, 1H), 7.52-7.60 (m, 3H).Enantiomeric excess: >98%.

(−)-N-[3-(Trifluoromethyl)benzyl)]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(compound 45)

[α²⁵ _(D)]=−132°, c=0.8, methanol. ¹H-NMR (400 MHz, CDCl₃) δ 0.83 (t,J=6.92 Hz, 3H), 1.15-1.30 (m, 4H), 1.51-1.65 (m, 2H), 2.81-2.99 (m, 3H),3.45 (dd, J=17.3 and 11.3 Hz, 1H), 4.46 (dd, J=14.4 and 11.4 Hz, 1H),4.59 (s, 2H), 7.28-7.39 (m, 5H), 7.43-7.50 (m, 1H), 7.52-7.60 (m, 3H).Enantiomeric excess: >98%.

Preparative chiral HPLC method: A 250×76 mm column was used. Stationaryphase: CHIRALPAK® IA 20 μm. n-Heptane/dichloromethane=75/25 (v/v) wasused as the mobile phase. Flow rate: 270 ml/minute. Temperature: 25° C.Detection UV 300 nm

Analytical HPLC monitoring system: A 250×4.6 mm column was used.Stationary phase: CHIRALPAK® IA-H 5 μm. n-Heptane/dichloromethane=75/25(v/v) was used as the mobile phase. Flow rate: 1 ml/minute. Temperature:25° C. Detection: Diode array detection (DAD) 254 and 300 nm.Enantiomeric excess: >98%

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-(4-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.81-0.94 (m, 10H), 0.97 (s, 3H), 1.07-1.47(m, 7H), 1.52-1.65 (m, 2H), 1.69 (t, J=4.4 Hz, 1H), 1.75-1.86 (m, 1H),2.33-2.43 (m, 1H), 2.73-2.84 (m, 1H), 2.88-2.96 (m, 2H), 3.35-3.51 (m,1H), 4.26-4.44 (m, 2H), 6.67 (br d, J=6 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H),7.31-7.39 (m, 2H).

N-[3-(trifluoromethyl)benzyl]-1-(n-pentyl)-5-(3-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.81-0.91 (m, 3H), 1.16-1.35 (m, 4H),1.52-1.65 (m, 2H), 2.84 (dd, J=17.4 and 14.1 Hz, 1H), 2.87-2.99 m, 2H),3.46 (dd, J=17.4 and 11.4 Hz, 1H), 4.45 (dd, J=14.1 and 11.4 Hz, 1H),4.60 (d, J=6.3 Hz, 2H), 7.01 (dt, J=8.1 and 2.1 Hz, 2H), 7.07-7.16 (m,2H), 7.33 (dt, J=7.9 and 5.8 Hz, 1H), 7.43-7.50 (m, 1H), 7.51-7.61 (m,3H).

N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-(n-pentyl)-5-(3-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.82-0.90 (m, 3H), 1.22-1.34 (m, 4H),1.54-1.67 (m, 2H), 1.73 (s, 3H), 1.74 (s, 3H), 2.73 (dd, J=17.4 and 14.1Hz, 1H), 2.93 (t, J=7.4 Hz, 2H), 3.35 (dd, J=17.4 and 11.1 Hz, 1H), 4.38(dd, J=14.3 and 11.3 Hz, 1H), 6.94 (br s, 1H), 6.96-7.05 (m, 3H),7.07-7.14 (m, 2H), 7.28-7.35 (m, 1H), 7.37-7.44 (m, 2H).

N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-(n-pentyl)-5-(4-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.82-0.90 (m, 3H), 1.20-1.31 (m, 4H),1.53-1.67 (m, 2H), 1.73 (s, 3H), 1.74 (s, 3H), 2.73 (dd, J=17.4 and 14.4Hz, 1H), 2.91 (t, J=7.4 Hz, 2H), 3.33 (dd, J=17.4 and 11.1 Hz, 1H), 4.36(dd, J=14.1 and 11.1 Hz, 1H), 6.95 (br s, 1H), 6.97-7.08 (m, 4H), 7.33(dd, J=8.7 and 5.4 Hz, 2H), 7.41 (dd, J=8.9 and 5.3 Hz, 2H).

N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-(n-propyl)-5-(3-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.89 (t, J=7.4 Hz, 3H), 1.55-1.71 (m, 2H),1.73 (s, 3H), 1.74 (s, 3H), 2.73 (dd, J=17.3 and 14.3 Hz, 1H), 2.83-2.97(m, 2H), 3.36 (dd, J=17.4 and 11.1 Hz, 1H), 4.38 (dd, J=14.3 and 11.3Hz, 1H), 6.94 (brs, 1H), 6.96-7.05 (m, 3H), 7.07-7.15 (m, 2H), 7.28-7.35(m, 1H), 7.40 (dd, J=8.7 and 5.4 Hz, 2H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(4,4,4-trifluorobutyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 1)

Compounds 51 and 52 were obtained from the corresponding diasteromericmixture via a flash chromatographic purification (silicagel). Eluant:petroleum ether (40-60)/ethylacetate=90/10 (v/v). Compound 52: second(slowest) eluting diastereomer: Compound 51: first (fastest) elutingdiastereomer.

¹H-NMR (400 MHz, CDCl₃) δ 0.82-0.95 (m, 7H), 0.98 (s, 3H), 1.22-2.11 (m,8H), 2.13-2.27 (m, 1H), 2.34-2.45 (m, 1H), 2.81-2.96 (m, 2H), 2.99-3.08(m, 1H), 3.44 (dd, J=17.4 and 11.1 Hz, 1H), 4.26-4.40 (m, 2H), 6.65 (brd, J=9 Hz, 1H), 7.30-7.42 (m, 5H). [α²⁵ _(D)]=102°, c=1, methanol.

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(4,4,4-trifluorobutyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 2)

¹H-NMR (400 MHz, CDCl₃) δ 0.83-0.94 (m, 7H), 0.97 (s, 3H), 1.20-1.32 (m,1H), 1.38-1.49 (m, 1H), 1.54-1.63 (m, 1H), 1.70 (t, J=4.4 Hz, 1H),1.75-1.88 (m, 2H), 1.89-2.08 (m, 2H), 2.13-2.29 (m, 1H), 2.32-2.44 (m,1H), 2.81-2.95 (m, 2H), 2.97-3.07 (m, 1H), 3.42 (dd, J=17.4 and 10.8 Hz,1H), 4.26-4.38 (m, 2H), 6.65 (br d, J=9.3 Hz, 1H), 7.29-7.41 (m, 5H).[α²⁵ _(D)]=−102°, c=1, methanol.

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-propyl-5-(3-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 1)

Compounds 53 and 54 were obtained from the corresponding diasteromericmixture via a flash chromatographic purification (silicagel). Eluantgradient: petroleum ether (40-60)/ethylacetate=95/5=>petroleum ether(40-60)/ethylacetate=90/10 (v/v). Compound 53: second (slowest) elutingdiastereomer: Compound 54: first (fastest) eluting diastereomer.

¹H-NMR (400 MHz, CDCl₃) δ 0.83-0.94 (m, 10H), 0.97 (s, 3H), 1.21-1.30(m, 1H), 1.36-1.47 (m, 1H), 1.54-1.73 (m, 4H), 1.74-1.86 (m, 1H),2.31-2.43 (m, 1H), 2.80 (dd, J=17.3 and 14.3 Hz, 1H), 2.85-2.99 (m, 2H),3.43 (dd, J=17.4 and 11.1 Hz, 1H), 4.25-4.35 (m, 1H), 4.38 (dd, J=14.1and 11.1 Hz, 1H) 6.66 (br d, J=9 Hz, 1H) 7.00 (br t, J=8.3 Hz, 1H),7.09-7.18 (m, 2H), 7.28-7.37 (m, 1H). [α²⁵ _(D)]=−122°, c=1, methanol.

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-propyl-5-(3-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 2)

¹H-NMR (400 MHz, CDCl₃) δ 0.82-0.93 (m, 10H), 0.97 (s, 3H), 1.21-1.31(m, 1H), 1.37-1.47 (m, 1H), 1.54-1.67 (m, 3H), 1.69 (t, J=4.4 Hz, 1H),1.74-1.86 (m, 1H), 2.31-2.43 (m, 1H), 2.79 (dd, J=17.4 and 14.1 Hz, 1H),2.85-2.99 (m, 2H), 3.44 (dd, J=17.1 and 11.1 Hz, 1H), 4.30 (br tt, J=9.1and 2.4 Hz, 1H), 4.40 (dd, J=14.0 and 11.3 Hz, 1H), 6.66 (br d, J=9 Hz,1H), 7.00 (dt, J=8.3 and 1.9 Hz, 1H), 7.08-7.15 (m, 2H), 7.31 (dd, J=7.8and 6 Hz, 1H). [α²⁵ _(D)]=145°, c=1, methanol.

N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-(4,4,4-trifluorobutyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 1.74 (s, 3H), 1.75 (s, 3H), 1.78-1.88 (m, 1H),1.89-2.06 (m, 2H), 2.14-2.26 (m, 1H), 2.80 (dd, J=17.4 and 14.4 Hz, 1H),2.85-2.93 (m, 1H), 2.98-3.06 (m, 1H), 3.35 (dd, J=17.4 and 10.8 Hz, 1H),4.32 (dd, J=14.6 and 11 Hz, 1H), 6.93 (br s, 1H), 7.02 (t, J=8.7 Hz,2H), 7.29-7.38 (m, 5H), 7.38-7.44 (m, 2H).

N-Cyclohexylmethyl-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7, 3H), 0.91-1.03 (m, 2H),1.10-1.34 (m, 7H), 1.47-1.70 (m, 4H), 1.70-1.81 (m, 4H), 2.80 (dd,J=17.1 and 13.8 Hz, 1H), 2.88-3.01 (m, 2H), 3.12-3.25 (m, 2H), 3.48 (dd,J=17.1 and 11.4 Hz, 1H), 4.73 (dd, J=13.8 and 11.4 Hz, 1H), 6.67 (br t,J˜6.5 Hz, 1H), 7.05 (dd, J=10.1 and 8.6 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H),7.24-7.31 (m, 1H), 7.48 (dt, J=7.5 and ˜2 Hz, 1H).

N-(Indan-2-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.81-0.86 (m, 3H), 1.13-1.31 (m, 4H) 1.51-1.64(m, 2H), 2.81 (dd, J=17.4 and 13.8 Hz, 1H), 2.86-2.97 (m, 4H), 3.32-3.41(m, 2H), 3.49 (dd, J=17.1 and 11.4 Hz, 1H), 4.74 (dd, J=13.7 and 11.6Hz, 1H), 4.78-4.87 (m, 1H), 6.78 (br d, J=8.1 Hz, 1H), 7.01-7.08 (m, 1H)7.12-7.17 (m, 1H), 7.17-7.22 (m, 2H), 7.22-7.31 (m, 3H), 7.42-7.49 (m,1H).

N-(Endo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.81-0.89 (m, 4H), 1.20-1.38 (m, 6H),1.43-1.52 (m, 2H), 1.53-1.70 (m, 4H), 2.06-2.17 (m, 1H), 2.24 (br t,J=4.5 Hz, 1H), 2.49 (br t, J=4.3 Hz, 1H), 2.79 (dd, J=17.3 and 13.7 Hz,1H), 2.89-3.03 (m, 2H), 3.48 (dd, J=17.4 and 11.4 Hz, 1H), 4.13-4.23 (m,1H), 4.70-4.78 (m, 1H), 6.63-6.69 (m, 1H), 7.02-7.08 (m, 1H), 7.13-7.18(m, 1H), 7.24-7.31 (m, 1H), 7.45-7.52 (m, 1H).

N-(Cycloheptyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7 Hz, 3H), 1.20-1.32 (m, 4H),1.46-1.71 (m, 11H), 1.92-2.03 (m, 2H), 2.74-2.84 (m, 2H), 2.90-2.98 (m,2H), 3.47 (dd, J=17.1 and 11.4 Hz, 1H), 3.96-4.07 (m, 1H), 4.72 (dd,J=13.8 and 11.1 Hz, 1H), 6.56 (br d, J=8.4 Hz, 1H), 7.01-7.08 (m, 1H),7.12-7.18 (m, 1H), 7.24-7.31 (m, 1H), 7.46-7.51 (m, 1H).

N-[3,4-difluorobenzyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.9 Hz, 3H), 1.17-1.33 (m, 4H),1.54-1.70 (m, 2H), 2.84 (dd, J=17.3 and 13.7 Hz, 1H), 2.88-3.02 (m, 2H),3.50 (dd, J=17.3 and 11.6 Hz, 1H), 4.43-4.54 (m, 2H), 4.79 (dd, J=13.8and 11.7 Hz, 1H), 6.96 (br t, J=6.3 Hz, 1H), 7.02-7.20 (m, 5H),7.25-7.32 (m, 1H), 7.47 (dt, J=7.5 and 1.8 Hz, 1H).

N-[Naphthalen-1-ylmethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.80 (t, J=6.9 Hz, 3H), 1.21 (m, 4H),1.49-1.61 (m, 2H), 2.79-2.97 (m, 3H), 3.53 (dd, J=17.1 and 11.4 Hz, 1H),4.71-4.80 (m, 1H), 4.95-5.06 (m, 2H), 6.84-6.90 (m, 1H)m 7.02-7.08 (m,1H), 7.15 (t, J=7.5 Hz, 1H), 7.24-7.31 (m, 1H), 7.42-7.61 (m, 5H), 7.83(d, J=8.1 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H).

N-[2-(Indol-3-yl)ethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=6.9 Hz, 3H), 1.17-1.32 (m, 4H),1.52-1.64 (m, 2H), 2.81 (dd, J=17.3 and 13.7 Hz, 1H), 2.86-2.98 (m, 2H),3.04 (t, J=6.9 Hz, 2H), 3.48 (dd, J=17.1 and 11.4 Hz, 1H), 3.68 (q,J=6.6 Hz, 2H), 4.68-4.78 (m, 1H), 6.77 (br t, J=6.2 Hz, 1H), 7.01-7.10(m, 2H), 7.14 (q, J=7.1 Hz, 2H), 7.21 (t, J=7.5 Hz, 1H), 7.24-7.31 (m,1H), 7.38 (d, J=8.1 Hz, 1H), 7.43-7.49 (m, 1H), 7.65 (d, J=7.8 Hz, 1H),8.06 (br s, 1H).

N-[(Pyridin-3-yl)methyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.81-0.89 (m, 3H), 1.15-1.33 (m, 4H),1.53-1.69 (m, 2H), 2.84 (dd, J=17.3 and 13.7 Hz, 1H), 2.89-3.02 (m, 2H),3.50 (dd, J=17.3 and 11.6 Hz, 1H), 4.51-4.60 (m, 2H) 4.79 (dd, J=13.8and 11.4 Hz, 1H), 6.98 (br t, J=6.5 Hz, 1H), 7.03-7.09 (m, 1H), 7.16 (t,J=7 Hz, 1H), 7.24-7.34 (m, 2H), 7.46 (dt, J=7.5 and 2 Hz, 1H), 7.69 (brd, J=7.8 Hz, 1H), 8.54 (br d, J=4.8 Hz, 1H), 8.58-8.62 (m, 1H).

N-[2-(Thien-2-yl)ethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.84-0.90 (m, 3H), 1.18-1.34 (m, 4H),1.56-1.67 (m, 2H), 2.80 (dd, J=17.1 and 13.8 Hz, 1H), 2.86-3.01 (m, 2H),3.10 (t, J=6.9 Hz, 2H), 3.48 (dd, J=17.1 and 11.4 Hz, 1H), 3.62 (q,J=6.6 Hz, 2H), 4.75 (dd, J=13.8 and 11.4 Hz, 1H), 6.79 (br t, J=6.3 Hz,1H), 6.88 (dd, J=3.2 and 1 Hz, 1H), 6.96 (dd, J=5.1 and 3.3 Hz, 1H),7.02-7.09 (m, 1H), 7.13-7.19 (m, 2H), 7.24-7.31 (m, 1H), 7.44-7.50 (m,1H).

N-[3,3-diphenylpropyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.87 (t, J=6.9 Hz, 3H), 1.20-1.34 (m, 4H),1.55-1.69 (m, 2H), 2.31-2.39 (m, 2H), 2.77 (dd, J=17.4 and 13.8 Hz, 1H),2.85-2.99 (m, 2H), 3.31 (q, J=8 Hz, 2H), 3.45 (dd, J=17.1 and 11.4 Hz,1H), 4.00 (t, J=7.8 Hz, 1H), 4.72 (dd, J=14 and 11.23 Hz, 1H), 6.59 (brt, J=6.6 Hz, 1H), 7.01-7.09 (m, 1H), 7.13-7.20 (m, 3H), 7.24-7.31 (m,9H), 7.47 (dt, J=7.5 and 2 Hz, 1H).

N-[(Furan-2-yl)methyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.82-0.90 (m, 3H), 1.17-1.35 (m, 4H),1.54-1.69 (m, 2H), 2.82 (dd, J=17.3 and 13.7 Hz, 1H), 2.87-3.01 (m, 2H),3.49 (dd, J=17.3 and 11.6 Hz, 1H), 4.48-4.60 (m, 2H), 4.76 (dd, J=13.7and 11.6 Hz, 1H), 6.26-6.37 (m, 2H), 6.90 (br t, J=6 Hz, 1H), 7.02-7.09(m, 1H), 7.12-7.18 (m, 1H), 7.24-7.32 (m, 1H), 7.36-7.40 (m, 1H), 7.46(dt, J=8.2 and 2 Hz, 1H).

N-Benzyl-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

1H-NMR (400 MHz, CDCl₃) δ 0.84 (t, J=6.9 Hz, 3H), 1.17-1.32 (m, 4H),1.54-1.66 (m, 2H), 2.84 (dd, J=17.1 and 13.8 Hz, 1H), 2.86-3.00 (m, 2H),3.51 (dd, J=17.4 and 11.4 Hz, 1H), 4.50-4.58 (m, 2H), 4.76 (dd, J=13.8and 11.4 Hz, 1H), 6.92 (br t, J=6 Hz, 1H), 7.02-7.09 (m, 1H), 7.16 (dt,J=7.5 and 1.2 Hz, 1H), 7.25-7.32 (m, 3H), 7.33-7.39 (m, 3H), 7.47 (dt,J=7.1 and 1.3 Hz, 1H).

N-Cyclopentyl-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=6.9 Hz, 3H), 1.18-1.35 (m, 4H),1.41-1.53 (m, 2H), 1.55-1.80 (m, 6H), 1.97-2.10 (m, 2H), 2.79 (dd,J=17.4 and 13.8 Hz, 1H), 2.87-3.01 (m, 2H), 3.48 (dd, J=17.4 and 11.4Hz, 1H), 4.27 (sextet, J=7.1 Hz, 1H), 4.72 (dd, J=14 and 11.3 Hz, 1H),6.54 (br d, J=7.8 Hz, 1H), 7.05 (dd, J=11 and 7.7 Hz, 1H), 7.15 (t,J=7.4 Hz, 1H), 7.24-7.32 (m, 1H), 7.48 (dt, J=7.4 and 1.6 Hz, 1H).

N-(4-Methoxybenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.84 (t, J=6.9 Hz, 3H), 1.17-1.32 (m, 4H),1.54-1.67 (m, 2H), 2.82 (dd, J=17.4 and 13.8 Hz, 1H), 2.87-2.99 (m, 2H),3.50 (dd, J=17.1 and 11.4 Hz, 1H), 3.81 (s, 3H), 4.46-4.49 (m, 2H), 4.75(dd, J=14.1 and 11.4 Hz, 1H), 6.82-6.91 (m, 3H), 7.05 (dd, J=11 and 7.7Hz, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.24-7.31 (m, 3H), 7.47 (dt, J=7.5 and1.8 Hz, 1H).

N-(2-Methoxybenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=6.9 Hz, 3H), 1.18-1.33 (m, 4H),1.56-1.67 (m, 2H), 2.80 (dd, J=17.1 and 13.8 Hz, 1H), 2.86-2.99 (m, 2H),3.49 (dd, J17.1 and 11.4 Hz, 1H), 3.88 (s, 3H), 4.52-4.56 (m, 2H), 4.73(dd, J=14 and 11.3 Hz, 1H), 6.87-6.96 (m, 2H), 7.05 (dd, J=9.8 and 8.9Hz, 1H), 7.08-7.18 (m, 2H), 7.23-7.34 (m, 3H), 7.47 (dt, J=7.6 and 2 Hz,1H).

N-[(1-ethyl)propyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.82-0.89 (m, 3H), 0.90-0.98 (m, 6H),1.19-1.34 (m, 4H), 1.39-1.53 (m, 2H), 1.54-1.70 (m, 4H), 2.81 (dd,J=17.1 and 13.8 Hz, 1H), 2.89-3.03 (m, 2H), 3.49 (dd, J=17.3 and 11.23Hz, 1H), 3.79-3.91 (m, 1H), 4.75 (dd, J=13.8 and 11.4 Hz, 1H), 6.38 (brd, J=9.3 Hz, 1H), 7.01-7.09 (m, 1H), 7.16 (t, J=7.5 Hz, 1H), 7.24-7.32(m, 1H), 7.49 (dt, J=7.5 and 1.8 Hz, 1H).

N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

1H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=6.9 Hz, 3H), 1.11-1.19 (m, 1H),1.19-1.33 (m, 7H), 1.38-1.69 (m, 5H), 1.79-1.87 (m, 1H), 2.26-2.33 (m,2H), 2.79 (dd, J=17.4 and 13.8 Hz, 1H), 2.88-3.01 (m, 2H), 3.47 (dd,J=17.4 and 11.4 Hz, 1H), 3.79 (dt, J=7.7 and 3.4 Hz, 1H), 4.68-4.77 (m,1H), 6.48 (br d, J=7.5 Hz, 1H), 7.05 (dd, J=9.8 and 8.6 Hz, 1H),7.12-7.18 (m, 1H), 7.24-7.31 (m, 1H), 7.44-7.51 (m, 1H).

N-(4-chlorobenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.84 (t, J=6.9 Hz, 3H), 1.16-1.32 (m, 4H),1.52-1.67 (m, 2H), 2.83 (dd, J=17.3 and 13.7 Hz, 1H), 2.88-3.01 (m, 2H),3.50 (dd, J=17.4 and 11.4 Hz, 1H), 4.46-4.55 (m, 2H), 4.78 (dd, J=13.8and 11.4 Hz, 1H), 6.95 (br t, J=6.3 Hz, 1H), 7.02-7.09 (m, 1H),7.12-7.19 (m, 1H), 7.24-7.34 (m, 5H), 7.46 (tt, J=7.5 and 2 Hz, 1H).

N-(1-Phenyl-ethyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(1:1 diasteromeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.80-0.90 (m, 3H), 1.17-1.33 (m, 4H),1.53-1.70 (m, 5H), 2.73-2.87 (m, 1H), 2.88-3.02 (m, 2H), 3.42-3.54 (m,1H), 4.69-4.80 (m, 1H), 5.20 (quintet, J=7.3 Hz, 1H), 6.85 (br d, J=8.4Hz, 1H), 7.01-7.08 (m, 1H), 7.11-7.19 (m, 1H), 7.23-7.31 (m, 2H),7.32-7.41 (m, 4H), 7.43-7.51 (m, 1H).

N-(Adamantylmethyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.84-0.89 (m, 3H), 1.21-1.35 (m, 4H),1.51-1.57 (m, 6H), 1.57-1.77 (m, 6H), 2.00 (br s, 3H), 2.81 (dd, J=17.4and 13.8 Hz, 1H), 2.90-3.10 (m, 4H), 3.49 (dd, J=17.1 and 11.4 Hz, 1H),4.75 (dd, J=14 and 11.23 Hz, 1H), 6.69 (t, J=6.8 Hz, 1H), 7.02-7.08 (m,1H), 7.16 (br t, J˜8, 1H), 7.24-7.31 (m, 1H), 7.49 (dt, J=7.4 and 2 Hz,1H).

N-(3,4-Dimethoxybenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.84 (t, J=6.9 Hz, 3H), 1.15-1.32 (m, 4H),1.54-1.66 (m, 2H), 2.83 (dd, J=17.1 and 13.8 Hz, 1H), 2.86-3.00 (m, 2H),3.51 (dd, J=17.3 and 11.6 Hz, 1H), 3.88 (s, 3H), 3.89 (s, 3H), 4.43-4.52(m, 2H), 4.76 (dd, J=14 and 11.6 Hz, 1H), 6.82-6.92 (m, 4H), 7.03-7.09(m, 1H), 7.16 (t, J=7.2 Hz, 1H), 7.25-7.32 (m, 1H), 7.47 (dt, J=7.5 and2 Hz, 1H).

N-(3-Fluorobenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.82-0.88 (m, 3H), 1.17-1.33 (m, 4H),1.53-1.71 (m, 2H), 2.84 (dd, J=17.3 and 13.7 Hz, 1H), 2.90-3.03 (m, 2H),3.51 (dd, J=17.3 and 11.6 Hz, 1H), 4.48-4.58 (m, 2H), 4.79 (dd, J=13.8and 11.4 Hz, 1H), 6.93-7.02 (m, 2H), 7.02-7.13 (m, 3H), 7.16 (t, J=7.5Hz, 1H), 7.25-7.35 (m, 2H), 7.47 (dt, J=7.5 and 2 Hz, 1H).

N-(2-Phenyl-propyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(1:1 diasteromeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7 Hz, 3H), 1.17-1.30 (m, 4H), 1.32(d, J=6.9 Hz, 3H), 1.52-1.63 (m, 2H), 2.72-3.06 (m, 4H), 3.34-3.51 (m,2H), 3.58-3.67 (m, 1H), 4.65-4.76 (m, 1H), 6.57 (br t, J=6.3 Hz, 1H),7.04 (dd, J=9.8 and 8.9 Hz, 1H), 7.11-7.17 (m, 1H), 7.21-7.30 (m, 4H),7.30-7.36 (m, 2H), 7.42-7.49 (m, 1H).

N-[2-(7-methyl-indol-3-yl)ethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=6.9 Hz, 3H), 1.18-1.31 (m, 4H),1.53-1.65 (m, 2H), 2.49 (s, 3H), 2.80 (dd, J=17.1 and 13.8 Hz, 1H),2.83-2.97 (m, 2H), 3.03 (t, J=7.1 Hz, 2H), 3.48 (dd, J=17.1 and 11.4 Hz,1H), 3.68 (q, J=6.9 Hz, 2H), 4.72 (dd, J=13.8 and 11.4 Hz, 1H), 6.78 (t,J=6.2 Hz, 1H), 6.99-7.09 (m, 4H), 7.15 (t, J=7.5 Hz, 1H), 7.24-7.31 (m,1H), 7.46 (dt, J=7.5 and 2 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 8.10 (br s,1H).

N-(3,4,5-Trimethoxybenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.84 (t, J=6.9 Hz, 3H), 1.18-1.31 (m, 4H),1.55-1.66 (m, 2H), 2.84 (dd, J=17.3 and 13.7 Hz, 1H), 2.89-3.01 (m, 2H),3.52 (dd, J=17.3 and 11.6 Hz, 1H), 3.84 (s, 3H), 3.87 (s, 6H), 4.42-4.52(m, 2H), 4.78 (dd, J=13.8 and 11.4 Hz, 1H), 6.57 (s, 2H), 6.91 (br t,J=6.2 Hz, 1H), 7.06 (dd, J=9.6 and 8.7 Hz, 1H), 7.16 (t, J=7.5 Hz, 1H),7.25-7.32 (m, 1H), 7.44-7.50 (m, 1H).

N-(Cyclooctyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=6.92 Hz, 3H), 1.18-1.34 (m, 4H),1.50-1.75 (m, 14H), 1.82-1.95 (m, 2H), 2.79 (dd, J=17.4 and 13.8 Hz,1H), 2.87-3.02 (m, 2H), 3.47 (dd, J=17.3 and 11.3 Hz, 1H), 4.01-4.11 (m,1H), 4.72 (dd, J=14 and 11.3 Hz, 1H), 6.57 (br d, J=8.4 Hz, 1H),7.01-7.09 (m, 1H), 7.12-7.18 (m, 1H), 7.24-7.31 (m, 1H), 7.45-7.51 (m,1H).

N-(tert-Butyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7.2 Hz, 3H), 1.20-1.33 (m, 4H),1.42 (s, 9H), 1.56-1.68 (m, 2H), 2.77 (dd, J=17.1 and 13.8 Hz, 1H), 2.92(br t, J=7.1 Hz, 2H), 3.45 (dd, J=17.3 and 11.3 Hz, 1H), 4.70 (dd, J=14and 11.3 Hz, 1H), 6.50 (br s,1H), 7.01-7.08 (m, 1H), 7.12-7.18 (m, 1H),7.24-7.31 (m, 1H), 7.48 (dt, J=7.5 and 1.8 Hz, 1H).

N-(2-(Trifluoromethyl)benzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

1H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.9 Hz, 3H), 1.17-1.33 (m, 4H),1.54-1.70 (m, 2H), 2.83 (dd, J=17.1 and 13.8 Hz, 1H), 2.88-3.02 (m, 2H),3.50 (dd, J=17.3 and 11.6 Hz, 1H), 4.67-4.82 (m, 3H), 6.99 (br t, J=6.6Hz, 1H), 7.02-7.09 (m, 1H), 7.15 (t, J=8.1 Hz, 1H), 7.25-7.31 (m, 1H),7.38 (t, J=7.7 Hz, 1H), 7.46 (dt, J=7.5 and 1.8 Hz, 1H), 7.54 (t, J=7.7Hz, 1H), 7.60-7.68 (m, 2H).

N-(5-Methyl-thiazol-2-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85-0.89 (m, 3H), 1.19-1.34 (m, 4H),1.59-1.69 (m, 2H), 2.40 (s, 3H), 2.93 (dd, J=17 and 13.1 Hz, 1H),2.97-3.14 (m, 2H), 3.56 (dd, J=17.1 and 12.3 Hz, 1H), 4.96 (t, J=12.6Hz, 1H), 7.05-7.12 (m, 2H), 7.18 (t, J=7.4 Hz, 1H), 7.28-7.34 (m, 1H),7.43 (dt, J=7.5 and 1.8 Hz, 1H), 10.02 (br s, 1H).

N-(3-Methoxybenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.84 (t, J=6.9 Hz, 3H), 1.17-1.32 (m, 4H),1.54-1.68 (m, 2H), 2.83 (dd, J=17.1 and 13.8 Hz, 1H), 2.88-3.00 (m, 2H),3.51 (dd, J=17.3 and 11.6 Hz, 1H), 3.81 (s, 3H), 4.48-4.57 (m, 2H), 4.76(dd, J=13.8 and 11.4 Hz, 1H), 6.81-6.85 (m, 1H), 6.87-6.95 (m, 3H),7.02-7.09 (m, 1H), 7.16 (t, J=6.9 Hz, 1H), 7.24-7.31 (m, 2H), 7.47 (dt,J=7.5 and 1.8 Hz, 1H).

N-[3-(Trifluoromethyl)benzyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.80-0.88 (m, 3H), 1.16-1.33 (m, 4H),1.53-1.69 (m, 2H), 2.85 (dd, J=17.3 and 13.7 Hz, 1H), 2.90-3.03 (m, 2H),3.51 (dd, J=17.1 and 11.7 Hz, 1H), 4.56-4.64 (m, 2H), 4.81 (dd, J=13.8and 11.7 Hz, 1H), 7.02-7.10 (m, 2H), 7.16 (t, J=7.5 Hz, 1H), 7.25-7.33(m, 1H), 7.43-7.50 (m, 2H), 7.52-7.57 (m, 2H), 7.58 (br s, 1H).

N-[(1R,2S,5R)-rel-6,6-dimethylbicyclo[3.1.1.]heptan-2-methyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(mixture of diastereoisomers) (from (−)-cis-myrtanylamine (CAS38235-68-6))

¹H-NMR (400 MHz, CDCl₃) δ 0.84-0.93 (m, 4H), 1.06 (s, 3H), 1.21 (d,J=2.4 Hz, 3H), 1.22-1.34 (m, 4H), 1.48-1.69 (m, 3H), 1.82-2.03 (m, 5H),2.22-2.32 (m, 1H), 2.34-2.42 (m, 1H), 2.75-2.85 (m, 1H), 2.88-3.01 (m,2H), 3.28-3.41 (m, 2H), 3.43-3.53 (m, 1H), 4.74 (dd, J=13.8 and 11.4 Hz,1H), 6.64 (br t, J=6.3 Hz, 1H), 7.02-7.08 (m, 1H), 7.15 (t, J=7.5 Hz,1H), 7.24-7.31 (m, 1H), 7.45-7.51 (m, 1H).

N-(Adamant-1-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7.1 Hz, 3H), 1.18-1.35 (m, 4H),1.52-1.75 (m, 8H), 2.05-2.13 (m, 9H), 2.75 (dd, J=17.3 and 14 Hz, 1H),2.92 (t, J=7.4 Hz, 2H), 3.44 (dd, J=17.3 and 11.3 Hz, 1H), 4.69 (dd,J=14 and 11.3 Hz, 1H), 6.39 (br s, 1H), 7.01-7.08 (m, 1H), 7.15 (t,J=7.4 Hz, 1H), 7.23-7.31 (m, 1H), 7.45-7.51 (m, 1H).

N-[1-phenyl-1-methyl-ethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=6.9 Hz, 3H), 1.19-1.35 (m, 4H),1.55-1.70 (m, 2H), 1.76 (s, 3H), 1.77 (s, 3H), 2.76 (dd, J=17.5 and 13.8Hz, 1H), 2.91-2.99 (m, 2H), 3.42 (dd, J=17.3 and 11.3 Hz, 1H), 4.72 (dd,J=14 and 11.3 Hz, 1H), 6.96 (br s, 1H), 7.01-7.07 (m, 1H), 7.15 (t,J=7.4 Hz, 1H), 7.20-7.30 (m, 2H), 7.34 (t, J=7.7 Hz, 2H), 7.42-7.52 (m,3H).

N-[4-(Trifluoromethyl)benzyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.9 Hz, 3H), 1.15-1.34 (m, 4H),1.53-1.69 (m, 2H), 2.85 (dd, J=17.3 and 13.7 Hz, 1H), 2.90-3.03 (m, 2H),3.51 (dd, J=17.3 and 11.6 Hz, 1H), 4.54-4.64 (m, 2H), 4.79 (dd, J=13.8and 11.4 Hz, 1H), 6.98-7.10 (m, 2H), 7.16 (t, J=7.5 Hz, 1H), 7.24-7.33(m, 1H), 7.43-7.50 (m, 3H), 7.60 (d, J=8.1 Hz, 2H).

N-[1-(Adamant-1-yl)-ethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.83-0.90 (m, 3H), 1.06-1.13 (m, 3H),1.20-1.36 (m, 4H), 1.49-1.77 (m, 14H), 1.98-2.04 (m, 3H), 2.81 (dd,J=17.3 and 14 Hz, 1H), 2.89-3.03 (m, 2H), 3.49 (dd, J=17.1 and 11.1 Hz,1H), 3.72-3.82 (m, 1H), 4.68-4.79 (m, 1H), 6.51 (br d, J=10.2 Hz, 1H),7.01-7.09 (m, 1H), 7.12-7.19 (m, 1H), 7.24-7.31 (m, 1H), 7.46-7.55 (m,1H).

N-(Noradamant-1-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.83-0.90 (m, 3H), 1.17-1.35 (m, 4H),1.51-1.71 (m, 6H), 1.91-1.98 (m, 2H), 2.01-2.10 (m, 2H), 2.10-2.19 (m,2H), 2.29 (br s, 2H), 2.50 (br t, J=6.8 Hz, 1H), 2.79 (dd, J=17.4 and13.8 Hz, 1H), 2.93 (t, J=7.2 Hz, 2H), 3.46 (dd, J=17.3 and 11.3 Hz, 1H),4.72 (dd, J=14 and 11.3 Hz, 1H), 6.79 (br s, 1H), 7.05 (ddd, J=10.2, 8.1and 1.2 Hz, 1H), 7.15 (br t, J=6.9 Hz, 1H), 7.24-7.32 (m, 1H), 7.48 (dt,J=7.5 and 2.1 Hz, 1H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5-(benzothien-3-yl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 1)

Compounds 93 and 94 were obtained from the corresponding diasteromericmixture via a Sepacore column (40×150 mm) chromatographic purification.Eluant gradient: petroleum ether (40-60)/diethyl ether=90/10=>petroleumether (40-60)/diethyl ether=80/20 (v/v)). Compound 93: first (fastest)eluting diastereomer: Compound 94: second (slowest) elutingdiastereomer:

¹H-NMR (400 MHz, CDCl₃) δ 0.82-1.02, (m, 13H), 1.20-1.49 (m, 4H),1.59-1.67 (m, 3H), 1.70 (t, J=4.5 Hz, 1H), 1.75-1.87 (m, 1H), 2.38 (m,1H), 2.91-3.11 (m, 3H), 3.51 (dd, J=17.4 and 11.4 Hz, 1H), 4.38-4.48 (m,1H), 4.80 (dd, J=14.4 and 11.4 Hz, 1H), 6.71 (br d, J=9.3 Hz, 1H), 7.37(dd, J=6.2 and 3.2 Hz, 2H), 7.40 (s, 1H), 7.75-7.81 (m, 1H), 7.86-7.91(m, 1H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5-(benzothien-3-yl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 2)

¹H-NMR (400 MHz, CDCl₃) δ 0.82-1.03 (m, 13H), 1.20-1.51 (m, 4H).1.62-1.68 (m, 3H), 1.70 (t, J=4.4 Hz, 1H), 1.76-1.88 (m, 1H), 2.34-2.47(m, 1H), 2.90-3.11 (m, 3H), 3.50 (dd, J=17.3 and 11.3 Hz, 1H), 4.27-4.37(m, 1H), 4.78 (dd, J=14.4 and 11.4 Hz, 1H), 6.71 (br d, J=9 Hz, 1H),7.35-7.45 (m, 3H), 7.77-7.83 (m, 1H), 7.86-7.92 (m, 1H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-(thien-3-yl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.83-0.93 (m, 10H), 0.97 (s, 3H), 1.20-1.34(m, 5H), 1.36-1.46 (m, 1H), 1.54-1.65 (m, 3H), 1.69 (t, J=4.5 Hz, 1H),1.73-1.86 (m, 1H), 2.32-2.42 (m, 1H), 2.80-2.90 (m, 1H), 2.90-3.04 (m,2H), 3.31-3.41 (m, 1H), 4.26-4.34 (m, 1H), 4.46-4.56 (m, 1H), 6.66 (brd, J=9 Hz, 1H), 7.08-7.13 (m, 1H), 7.18-7.22 (m, 1H), 7.31-7.35 (m, 1H).

N-(1-phenyl-1-methyl-ethyl)-1-(n-pentyl)-5-(thien-3-yl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.83-0.90 (m, 3H), 1.20-1.33 (m, 4H),1.53-1.68 (m, 2H), 1.76 (s, 3H), 1.77 (s, 3H), 2.80 (dd, J=17.1 and 14.1Hz, 1H), 2.87-3.01 (m, 2H), 3.29 (dd, J=17.1 and 10.8 Hz, 1H), 4.49 (dd,J=14.1 and 10.8 Hz, 1H), 6.96 (br s, 1H), 7.08-7.12 (m, 1H), 7.18-7.21(m, 1H), 7.23 (br t, J=7.2 Hz, 1H), 7.30-7.38 (m, 3H), 7.45 (br d, J=7.2Hz, 2H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-propyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 1)

Compounds 97 and 98 were obtained from the corresponding diasteromericmixture via a Sepacore column (40×150 mm) chromatographic purification.Eluant gradient: petroleum ether (40-60)/diethyl ether=90/10=>petroleumether (40-60)/diethyl ether=60/40 (v/v)). Compound 97: second (slowest)eluting diastereomer: Compound 98: first (fastest) eluting diastereomer.

¹H-NMR (400 MHz, CDCl₃) δ 0.84-0.93 (m, 10H), 0.97 (s, 3H), 1.21-1.30(m, 1H), 1.38-1.47 (m, 1H), 1.56-1.68 (m, 3H), 1.70 (t, J=4.4 Hz, 1H),1.76-1.86 (m, 1H), 2.33-2.43 (m, 1H), 2.80 (dd, J=17.4 and 14.4 Hz, 1H),2.82-2.98 (m, 2H), 3.46 (dd, J=17.4 and 11.1 Hz, 1H), 4.26-4.34 (m, 1H),4.45 (dd, J=14.4 and 11.1 Hz, 1H), 6.67 (br d, J=9.1 Hz, 1H), 7.46-7.51(m, 1H), 7.55-7.61 (m, 2 H), 7.67 (br s, 1H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-propyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 2)

¹H-NMR (400 MHz, CDCl₃) δ 0.82-0.94 (m, 10H), 0.97 (s, 3H), 1.20-1.35(m, 1H), 1.38-1.48 (m, 1H), 1.54-1.67 (m, 3H), 1.69 (t, J=4.4 Hz, 1H),1.75-1.86 (m, 1H), 2.33-2.42 (m, 1H), 2.79 (dd, J=17.3 and 14.3 Hz, 1H),2.85-3.00 (m, 2H), 3.48 (dd, J=17.4 and 11.4 Hz, 1H), 4.25-4.35 (m, 1H),4.47 (dd, J=14.1 and 11.1 Hz, 1H), 6.68 (br d, J=9.1 Hz, 1H), 7.46-7.51(m, 1H), 7.55-7.60 (m, 2H), 7.65 (br s, 1H).

N-(1-phenyl-1-methyl-ethyl)-1-(n-propyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.4 Hz, 3H), 1.55-1.71 (m, 2H),1.76 (s, 3H), 1.77 (s, 3H), 2.75 (dd, J=17.4 and 14.4 Hz, 1H), 2.80-2.98(m, 2H), 3.41 (dd, J=17.4 and 11.1 Hz, 1H), 4.44 (dd, J=14.4 and 11.1Hz, 1H), 6.97 (br s, 1H), 7.21-7.27 (m, 1H), 7.35 (br t, J=7.7 Hz, 2H),7.43-7.52 (m, 3H), 7.55-7.60 (m, 2H), 7.65 (br s, 1H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-(3-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(1:1 diastereomeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.81-0.94 (m, 10H), 0.97 (s, 3H), 1.20-1.35(m, 5H), 1.37-1.47 (m, 1H), 1.54-1.65 (m, 3H), 1.67-1.72 (m, 1H),1.75-1.87 (m, 1H), 2.32-2.42 (m, 1H), 2.73-2.84 (m, 1H), 2.91-2.99 (m,2H), 3.38-3.49 (m, 1H), 4.26-4.45 (m, 2H), 6.66 (br d, J=6.6 Hz, 1H),7.00 (dt, J=8.4 and 2.4 Hz, 1H), 7.08-7.17 (m, 2H), 7.28-7.35 (m, 1H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

To a magnetically stirred solution ofE-2-oxo-4-(2-fluorophenyl)-but-3-enoic acid[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamide](Intermediate X-3) (1.5 g, 4.83 mmol) in ethanol (50 ml) wassuccessively added acetic acid (660 ml, 11.58 mmol) andn-pentylhydrazine (Intermediate XI-1) (1.45 ml, 9.65 mmol) and theresulting mixture was reacted in a nitrogen atmosphere at 60° C. for 8hours in an oil bath. The reaction mixture was allowed to attain roomtemperature and concentrated in vacuo. The residue was dissolved indichloromethane, washed with water and subsequently dried over MgSO₄,filtered and concentrated in vacuo. Further chromatographic purificationusing Sepacore equipment (eluant: petroleum ether/ethylacetate=95/5(v/v)) gave compound 101 (940 mg, 46% yield) as an oil.

¹H-NMR (400 MHz, CDCl₃) δ 0.83-0.94 (m, 10H), 1.20-1.85 (m, 14H),2.32-2.42 (m, 1H), 2.74-2.85 (m, 1H), 2.91-3.02 (m, 2H), 3.43-3.54 (m,1H), 4.26-4.36 (m, 1H), 4.69-4.80 (m, 1H), 6.63-6.70 (m, 1H), 7.02-7.09(m, 1H), 7.12-7.19 (m, 1H), 7.25-7.31 (m, 1H), 7.46-7.54 (m, 1H).

N-(1-phenyl-1-methyl-ethyl)-1-(n-butyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

Compound 102 was obtained from E-2-oxo-4-phenyl-but-3-enoic acid[1-phenyl-1-methyl-ethyl]amide and n-butylhydrazine analogously to theprocedure described for compound 101.

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7, 3H), 1.20-1.39 (m, 2H),1.53-1.63 (m, 2H), 1.76 (s, 3H), 1.77 (s, 3H), 2.77 (dd, J=17 and 14,1H), 2.90-2.96 (m, 2H), 3.35 (dd, J=17 and 11, 1H), 4.37 (dd, J=14 and11, 1H), 6.97 (br s, 1H), 7.21-7.48 (m, 10H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

Compound 103 was obtained from E-2-oxo-4-phenyl-but-3-enoic acid[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamide](Intermediate X-2) and n-butylhydrazine analogously to the proceduredescribed for compound 101.

¹H-NMR (400 MHz, CDCl₃) δ 0.83-0.95 (m, 10H), 0.97 (s, 3H), 1.21-1.86(m, 9H), 2.32-2.42 (m, 1H), 2.77-2.88 (m, 1H), 2.91-2.99 (m, 2H),3.35-3.46 (m, 1H), 4.26-4.46 (m, 2H), 6.66 (br d, J˜8, 1H), 7.28-7.40(m, 5H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

Compound 104 was obtained from E-2-oxo-4-phenyl-but-3-enoic acid[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamide](Intermediate X-2) and n-pentylhydrazine (Intermediate XI-1) analogouslyto the procedure described for compound 101.

¹H-NMR (400 MHz, CDCl₃) δ 0.83-0.94 (m, 10H), 0.97 (s, 3H), 1.20-1.47(m, 5H), 1.54-1.65 (m, 3H), 1.69 (t, J˜6, 1H), 1.75-1.85 (m, 1H),2.32-2.42 (m, 1H), 2.82 (dd, J=17 and 14, 1H), 2.92-2.98 (m, 2H), 3.41(dd, J=17 and 11, 1H), 4.26-4.35 (m, 1H), 4.41 (dd, J=14 and 11, 1H),6.67 (br d, J˜8, 1H), 7.28-7.39 (m, 5H).

N-(1-(4-fluorophenyl)-1-methyl-ethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

Compound 6 was obtained from E-2-oxo-4-phenyl-but-3-enoic acid[1-(4-fluorophenyl)-1-methyl-ethyl]amide and n-pentylhydrazine(Intermediate XI-1) analogously to the method described for compound101.

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7, 3H), 1.20-1.31 (m, 4H),1.54-1.67 (m, 2H), 1.74 (s, 3H), 1.75 (s, 3H), 2.77 (dd, J=17 and 14,1H), 2.90-2.97 (m, 2H), 3.35 (dd, J=17 and 11, 1H), 4.38 (dd, J=14 and11, 1H), 6.94 (br s, 1H), 6.98-7.04 (m, 2H), 7.27-7.43 (m, 7H).

N-(2-(4-fluorophenyl)-1,1-dimethyl-ethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

Compound 106 was obtained from E-2-oxo-4-phenyl-but-3-enoic acid[2-(4-fluorophenyl)-2,2-dimethyl-ethyl]amide (Intermediate X-4) andn-pentylhydrazine (Intermediate XI-1) analogously to the proceduredescribed for compound 101.

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7, 3H), 1.16-1.27 (m, 4H), 1.36 (s,3H), 1.39 (s, 3H), 1.50-1.62 (m, 2H), 2.77-2.94 (m, 4H), 3.04 (d, J=13,1H), 3.10 (d, J=13, 1H), 3.41 (dd, J=18 and 12, 1H), 4.39 (dd, J=14 and11, 1H), 6.38 (br s, 1H), 6.94-7.01 (m, 2H), 7.10-7.16 (m, 2H),7.28-7.38 (m, 5H).

Furthermore, the compounds 107-118 were obtained analogously to themethod described for compound 101.

N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-isobutyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz,3H), 1.73 (s, 3H), 1.75 (s, 3H), 1.96-2.07 (m, 1H), 2.54 (dd, J=12.6 and9 Hz, 1H), 2.77 (dd, J=17.4 and 14.1 Hz, 1H), 2.84 (dd, J=12.6 and 5.1Hz, 1H), 3.34 (dd, J=17.4 and 11.1 Hz, 1H), 4.34 (dd, J=14.4 and 11.1Hz, 1H), 6.93 (br s, 1H), 7.01 (t, J=8.9 Hz, 2H), 7.27-7.37 (m, 5H),7.38-7.44 (m, 2H).

N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-cyclohexylmethyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.67-0.90 (m, 2H), 1.05-1.29 (m, 4H),1.51-1.72 (m, 4H), 1.74 (s, 3H), 1.75 (s, 3H), 1.82-1.90 (m, 1H), 2.61(dd, J=12.8 and 8.9 Hz, 1H), 2.76 (dd, J=17.3 and 14.3 Hz, 1H), 2.83(dd, J=12.6 and 5.1 Hz, 1H), 3.33 (dd, J=17.3 and 11 Hz, 1H), 4.33 (dd,J=14.4 and 11.1 Hz, 1H), 6.93 (br s, 1H), 7.01 (t, J=8.7 Hz, 2H),7.27-7.37 (m, 5H), 7.39-7.43 (m, 2H).

N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-phenethyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 1.74 (s, 3H), 1.75 (s, 3H), 2.77 (dd, J=17.4and 14.4 Hz, 1H), 2.84-2.93 (m, 1H), 2.95-3.03 (m, 1H), 3.13-3.29 (m,2H), 3.33 (dd, J=17.4 and 11.1 Hz, 1H), 4.43 (dd, J=14.4 and 11.1 Hz,1H), 6.91 (br s, 1H), 7.02 (t, J=8.7 Hz, 2H), 7.14 (d, J=6.9 Hz, 2H),7.16-7.35 (m, 8H), 7.38-7.44 (m, 2H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-isobutyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, DMSO-d₆) δ 0.81-0.95 (m, 13H), 0.96 (s, 3H), 1.22-1.30(m, 1H), 1.37-1.47 (m, 1H), 1.55-1.67 (m, 1H), 1.69 (t, J=4.5 Hz, 1H),1.75-1.85 (m, 1H), 1.96-2.08 (m, 1H), 2.32-2.43 (m, 1H), 2.52-2.60 (m,1H), 2.78-2.88 (m, 2H), 3.36-3.46 (m, 1H), 4.26-4.41 (m, 2H), 6.67 (brd, J˜8 Hz, 1H), 7.27-7.40 (m, 5H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-cyclohexylmethyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, DMSO-d₆) δ 0.70-0.95 (m, 9H), 0.98 (s, 3H), 1.04-1.32(m, 5H), 1.37-1.48 (m, 1H), 1.55-1.90 (m, 8H), 2.32-2.43 (m, 1H),2.60-2.70 (m, 1H), 2.77-2.89 (m, 2H), 3.35-3.46 (m, 1H), 4.26-4.42 (m,2H), 6.65 (br d, J˜9 Hz, 1H), 7.27-7.39 (m, 5H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(2-cyano-ethyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, DMSO-d₆) δ 0.82-0.95 (m, 7H), 0.97 (s, 3H), 1.22-1.32(m, 1H), 1.38-1.49 (m, 1H), 1.54-1.65 (m, 1H), 1.70 (t, J=4.7 Hz, 1H),1.75-1.88 (m, 1H), 2.34-2.44 (m, 1H), 2.61-2.77 (m, 2H), 2.88 (dd,J=17.6 and 14.3 Hz, 1H), 3.20 (t, J=6.8 Hz, 2H), 3.46 (dd, J=17.4 and10.8 Hz, 1H), 4.26-4.35 (m, 1H), 4.39 (dd, J=14.4 and 10.8 Hz, 1H), 6.67(br d, J=9 Hz, 1H), 7.31-7.44 (m, 5H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-phenethyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomeric mixture)

¹H-NMR (400 MHz, DMSO-d₆) δ 0.85-0.96 (m, 7H), 0.98 (s, 3H), 1.20-1.32(m, 1H), 1.39-1.48 (m, 1H), 1.55-1.65 (m, 1H) 1.70 (t, J=4.5 Hz, 1H),1.76-1.88 (m, 1H) 2.33-2.43 (m, 1H), 2.77-2.93 (m, 2H), 2.95-3.04 (m,1H), 3.16-3.30 (m, 2H), 3.42 (dd, J=17.4 and 11.1 Hz, 1H), 4.26-4.35 (m,1H), 4.45 (dd, J=14.4 and 11.1 Hz, 1H), 6.65 (br d, J=9.3 Hz, 1H),7.10-7.40 (m, 10H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5-(4-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 1)

Compounds 114 and 115 were obtained from the corresponding diasteromericmixture via a flash chromatographic purification. Eluant: petroleumether (40-60)/diethyl ether=75/25. Compound 115: first (fastest) elutingdiastereomer): Compound 114: second (slowest) eluting diastereomer.

¹H-NMR (400 MHz, CDCl₃) δ 0.81-0.93 (m, 10H), 0.97 (s, 3H), 1.08-1.65(m, 7H), 1.69 (t, J=4.5 Hz, 1H), 1.74-1.85 (m, 1H), 2.33-2.42 (m, 1H),2.78 (dd, J=17.1 and 14.4 Hz, 1H), 2.92 (t, J=7.4 Hz, 2H), 3.40 (dd,J=17.4 and 11.1 Hz, 1H), 4.26-4.34 (m, 1H), 4.36 (dd, J=14.4 and 11.1Hz, 1H), 6.65 (br d, J=9.3 Hz, 1H), 7.33 (s, 4H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5-(4-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(diastereomer 2)

¹H-NMR (400 MHz, CDCl₃) δ 0.82-0.93 (m, 10H), 0.97 (s, 3H), 1.18-1.63(m, 7H), 1.69 (t, J=4.5 Hz, 1H), 1.75-1.85 (m, 1H), 2.32-2.42 (m, 1H),2.77 (dd, J=17.3 and 14.3 Hz, 1H), 2.93 (t, J=7.4 Hz, 2H), 3.37-3.46 (m,1H), 4.26-4.34 (m, 1H), 4.38 (dd, J=14.1 and 11.1 Hz, 1H), 6.66 (br d,J=9.3 Hz, 1H), 7.29-7.35 (m, 4H).

N-[1-phenyl-1-methyl-ethyl]-1-n-butyl-5-(4-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7.4 Hz, 3H), 1.20-1.38 (m, 2H),1.53-1.63 (m, 2H), 1.76 (s, 3H), 1.77 (s, 3H), 2.72 (dd, J=17.3 and 14.3Hz, 1H), 2.90 (t, J=7.4 Hz, 2H), 3.34 (dd, J=17.4 and 11.1 Hz, 1H), 4.34(dd, J=14.4 and 11.1 Hz, 1H), 6.95 (br s, 1H), 7.20-7.26 (m, 1H),7.28-7.37 (m, 6H), 7.45 (d, J=7.8 Hz, 2H).

N-(1-(4-fluorophenyl)-1-methyl-ethyl)-1-(n-butyl)-5-(3-methoxyphenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide

¹H-NMR (400 MHz, CDCl₃) δ 0.85-0.89 (m, 3H), 1.22-1.39 (m, 2H),1.55-1.66 (m, 2H), 1.73 (s, 3H), 1.74 (s, 3H), 2.76 (dd, J=17.3 and 14.5Hz, 1H), 2.88-3.01 (m, 2 H), 3.33 (dd, J=17.3 and 11.1 Hz, 1H), 3.80 (s,3H), 4.35 (dd, J=14.5 and 11.1 Hz, 1H), 6.84 (ddd, J=8.12, 2.4 and 1.1Hz, 1H), 6.91-6.96 (m, 3H), 6.97-7.05 (m, 2H), 7.23-7.28 (m, 1H),7.38-7.44 (m, 2H).

N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5-(3-methoxyphenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide(1:1 diastereomeric mixture)

¹H-NMR (400 MHz, CDCl₃) δ 0.84-0.94 (m, 10H), 0.97 (s, 3H), 1.22-1.47(m, 4H), 1.54-1.66 (m, 3H), 1.69 (t, J=4.4 Hz, 1H), 1.75-1.86 (m, 1H),2.32-2.43 (m, 1H), 2.76-2.87 (m, 1H), 2.89-3.03 (m, 2H), 3.36-3.45 (m,1H), 3.81/3.82 (double s, 3H), 4.26-4.43 (m, 2H), 6.63-6.71 (m, 1H),6.81-6.87 (m, 1H), 6.92-6.97 (m, 2H), 7.23-7.30 (m, 1H).

Example 5 Pharmacological Methods

In Vitro Affinity for Cannabinoid-CB₁ Receptors

The affinity of the compounds of the invention for cannabinoid CB₁receptors can be determined using membrane preparations of Chinesehamster ovary (CHO) cells in which the human cannabinoid CB₁ receptor isstably transfected in conjunction with [³H]CP-55,940 as radioligand.After incubation of a freshly prepared cell membrane preparation withthe [³H]-ligand, with or without addition of one or more compounds ofthe invention, separation of bound and free ligand is performed byfiltration over glassfiber filters. Radioactivity on the filter ismeasured by liquid scintillation counting.

In Vitro Affinity for Cannabinoid-CB₂ Receptors

The affinity of the compounds of the invention for cannabinoid CB₂receptors can be determined using membrane preparations of CHO cells inwhich the human cannabinoid CB₂ receptor is stably transfected inconjunction with [³H]CP-55,940 as radioligand. After incubation of afreshly prepared cell membrane preparation with the [³H]-ligand, with orwithout addition of one or more compounds of the invention, separationof bound and free ligand is performed by filtration over glassfiberfilters. Radioactivity on the filter is measured by liquid scintillationcounting.

In Vitro Cannabinoid-CB₁ Receptor (Ant)Agonism

In vitro CB₁ receptor antagonism/agonism can be assessed with the humanCB₁ receptor cloned in CHO cells. CHO cells are grown in a Dulbecco'sModified Eagle's medium (DMEM) culture medium, supplemented with 10%heat-inactivated fetal calf serum. Medium is aspirated and replaced byDMEM, without fetal calf serum, but containing [³H]-arachidonic acid andincubated overnight in a cell culture stove (5% CO₂/95% air; 37° C.;water-saturated atmosphere). During this period [³H]-arachidonic acid isincorporated in membrane phospholipids. On the test day, medium isaspirated and cells are washed three times using 0.5 ml DMEM, containing0.2% bovine serum albumin (BSA). CB₁ agonist stimulation leads toactivation of PLA₂ followed by release of [³H]-arachidonic acid into themedium. This CB₁ agonist-induced release is concentration-dependentlyantagonized by CB₁ receptor antagonists, such as for example rimonabant.

In Vitro Cannabinoid-CB₂ Receptor (Ant)Agonism

Functional activity at the cannabinoid CB₂ receptor was assessed using aforskolin-stimulated cAMP accumulation assay. The ability of compoundsto stimulate and inhibit adenylate cyclase activity was assessed inChinese ovarian hamster (CHO) K₁ cells expressing human CB2 (Euroscreen,Brussel) receptor. CHO cells were grown in a CHO-S-SFM-II culturemedium, supplemented with 10% heat-inactivated foetal calf serum, 2 mMglutamine, 400 μg/ml Hygromycine B and 500 μg/ml G418 at 37° C. in 93%air/5% CO₂. For incubation with test compounds, confluent cultures grownin 24 well plates were used. Each condition or substance was routinelytested in quadruplicate. Cells were loaded with 1 mCi [³H]-adenine in0.5 ml medium per well. After 2 hours, cultures were washed with 0.5 mlPBS containing 1 mM IBMX and incubated for 20 minutes with 0.5 ml PBScontaining 1 mM IBMX and 3×10⁻⁷ M forskolin with or without the testcompound. Antagonistic effects of test compounds were determined asinhibition of 0.1 μM JWH-133-decreased [³H]cAMP formation. Afteraspiration the reaction was stopped with 1 ml trichloroacetic acid (5%w/v). The [³H]-ATP and [³H]-cAMP formed in the cellular extract wereassayed as follows: a volume of 0.8 ml of the extract was passed overDowex (50WX-4200-400 mesh) and aluminum oxide columns, eluted with waterand 0.1M imidazole (pH=7.5). Eluates were mixed with 7 ml Ultima-Flo[AP] and the β-radioactivity was counted with a liquid scintillationcounter. The conversion of [³H]-ATP into [³H]-cAMP was expressed as theratio in percentage radioactivity in the cAMP fraction as compared tothe combined radioactivity in both cAMP and ATP fractions, and basalactivity was subtracted to correct for spontaneous activity. Referencecompounds used to assess cannabinoid CB₂ receptor mediated adenylatecyclase activity were the full cannabinoid CB₂ receptor agonists JWH-133(Huffman, 1999^(b)) and WIN 55,212-2 (Huffman, 1999^(a)), and theinverse agonist or antagonist SR-144528 (Rinaldi-Carmona, 1998).Compounds were studied in a concentration range of 10⁻¹⁰ M to 10⁻⁶M.pEC₅₀ and the pA₂ were calculated according to Cheng-Prusoff equation(Cheng and Prusoff, 1973). Two independent experiments were performed intriplicate.

Example 6 Pharmacological Test Results

Affinity for CB₁- and CB₂- receptors, and in vitro agonistic activity onCB₁- receptors receptor binding Functional CB₁ assays Human CB₁ HumanCB₂ Human CB₁ affinity affinity agonism Cmp pK_(i) pK_(i) pEC₅₀ 1 8.18.3 8.1 4 7.5 7.1 7.4 7 6.9 6.3 6.2 12 7.1 7.4 7.4 14 7.5 6.6 6.3 22 7.26.5 7.1 27 7.8 8.1 7.9 28 8.2 7.0 8.1 32 8.1 8.0 7.4 37 7.8 7.0 8.1 1018.2 8.1 8.2 102 7.4 7.4 7.0 103 7.1 7.6 7.5 104 8.2 7.6 8.5 105 7.8 6.98.8 108 7.6 7.5 7.8 110 7.3 7.3 6.5

The compounds of the invention have a high affinity for cannabinoid-CB₁and CB₂ receptors, and are agonists on CB₁ receptors. Surprising,because 1,3,5-trisubstituted pyrazoline derivatives described in e.g.,WO 2005/074920, WO 2005/077911 and WO 2007/009689, as cannabinoid CB₁receptor ‘modulating’ agents, a definition embracing agonists,invariably were shown to be antagonists.

Example 7 Pharmaceutical Preparations

For clinical use, compounds of formula (I) can be formulated intopharmaceutical compositions that are important and novel embodiments ofthe invention because they contain the compounds, more particularlyspecific compounds disclosed herein. Types of pharmaceuticalcompositions that may be used include, but are not limited to, tablets,chewable tablets, capsules (including microcapsules), solutions,parenteral solutions, ointments (creams and gels), suppositories,suspensions, and other types disclosed herein or apparent to a personskilled in the art from the specification and general knowledge in theart. The active ingredient, for instance, may also be in the form of aninclusion complex in cyclodextrins, their ethers or their esters. Thecompositions are used for oral, intravenous, subcutaneous, tracheal,bronchial, intranasal, pulmonary, transdermal, buccal, rectal,parenteral or other ways to administer. The pharmaceutical formulationcontains at least one compound of formula (I) in a mixture with apharmaceutically acceptable adjuvant, diluent and/or carrier. In oneembodiment, the total amount of active ingredients may be in amounts,for example, from about 0.1% (w/w) to about 95% (w/w) of theformulation, and from 0.5% to 50% (w/w), and further from 1% to 25%(w/w).

The compounds of the invention can be brought into forms suitable foradministration by means of usual processes using auxiliary substancessuch as liquid or solid, powdered ingredients, such as thepharmaceutically customary liquid or solid fillers and extenders,solvents, emulsifiers, lubricants, flavorings, colorings and/or buffersubstances. Frequently used auxiliary substances include magnesiumcarbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol andother sugars or sugar alcohols, talc, lactoprotein, gelatin, starch,amylopectin, cellulose and its derivatives, animal and vegetable oilssuch as fish liver oil, sunflower, groundnut or sesame oil, polyethyleneglycol and solvents such as, for example, sterile water and mono- orpolyhydric alcohols such as glycerol, as well as with disintegratingagents and lubricating agents such as magnesium stearate, calciumstearate, sodium stearyl fumarate and polyethylene glycol waxes. Themixture may then be processed into granules or pressed into tablets. Atablet is prepared using the ingredients below:

Ingredient Quantity (mg/tablet) COMPOUND No. 1 10 Cellulose,microcrystalline 200 Silicon dioxide, fumed 10 Stearic acid 10 Total 230

The components are blended and compressed to form tablets each weighing230 mg.

The active ingredients may be separately premixed with the othernon-active ingredients, before being mixed to form a formulation. Theactive ingredients may also be mixed with each other, before being mixedwith the non-active ingredients to form a formulation.

Soft gelatin capsules may be prepared with capsules containing a mixtureof the active ingredients of the invention, vegetable oil, fat, or othersuitable vehicle for soft gelatin capsules. Hard gelatin capsules maycontain granules of the active ingredients. Hard gelatin capsules mayalso contain the active ingredients together with solid powderedingredients such as lactose, saccharose, sorbitol, mannitol, potatostarch, corn starch, amylopectin, cellulose derivatives or gelatin.

Dosage units for rectal administration may be prepared (i) in the formof suppositories that contain the active substance mixed with a neutralfat base; (ii) in the form of a gelatin rectal capsule that contains theactive substance in a mixture with a vegetable oil, paraffin oil orother suitable vehicle for gelatin rectal capsules; (iii) in the form ofa ready-made micro enema; or (iv) in the form of a dry micro enemaformulation to be reconstituted in a suitable solvent just prior toadministration.

Liquid preparations may be prepared in the form of syrups, elixirs,concentrated drops or suspensions, e.g. solutions or suspensionscontaining the active ingredients and the remainder consisting, forexample, of sugar or sugar alcohols and a mixture of ethanol, water,glycerol, propylene glycol and polyethylene glycol. If desired, suchliquid preparations may contain coloring agents, flavoring agents,preservatives, saccharine and carboxymethyl cellulose or otherthickening agents. Liquid preparations may also be prepared in the formof a dry powder, reconstituted with a suitable solvent prior to use.Solutions for parenteral administration may be prepared as a solution ofa formulation of the invention in a pharmaceutically acceptable solvent.These solutions may also contain stabilizing ingredients, preservativesand/or buffering ingredients. Solutions for parenteral administrationmay also be prepared as a dry preparation, reconstituted with a suitablesolvent before use.

Also provided according to the present invention are formulations and‘kits of parts’ comprising one or more containers filled with one ormore of the ingredients of a pharmaceutical composition of theinvention, for use in medical therapy. Associated with such container(s)can be various written materials such as instructions for use, or anotice in the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals products, which noticereflects approval by the agency of manufacture, use, or sale for humanor veterinary administration. The use of formulations of the inventionin the manufacture of medicaments for use in the treatment of acondition in which activation of cannabinoid CB₁ receptors is requiredor desired, and methods of medical treatment or comprising theadministration of a therapeutically effective total amount of at leastone compound of formula (I), to a patient suffering from, or susceptibleto, a condition in which activation of cannabinoid CB₁ receptors isrequired or desired.

By way of example and not of limitation, several pharmaceuticalcompositions are given, comprising exemplary active compounds forsystemic use or topical application. Other compounds of the invention orcombinations thereof, may be used in place of (or in addition to) saidcompounds. The concentration of the active ingredient may be varied overa wide range as discussed herein. Amounts and types of ingredients thatmay be included are known in the art.

Bibliography

To the extent in which the following references are useful to oneskilled in the art, or to more fully describe this invention, they areincorporated herein by reference. Neither these, nor any other documentsor quotes cited herein, nor citations to any references, are admitted tobe prior art documents or citations.

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1. A compound of formula (I)

or a tautomer, stereoisomer, N-oxide, or a pharmacologically acceptablesalt of any of the foregoing, wherein: R₁ is chosen from: C₃₋₁₀ linearalkyl, C₄₋₁₀ branched alkyl, C₄₋₁₀ alkenyl, C₄₋₁₀ alkynyl,C₃₋₁₀-heteroalkyl, C₅₋₈-cycloalkyl-C₁₋₅-alkyl, andC₅₋₈-heterocycloalkyl-C₁₋₅-alkyl, each of which may be optionallysubstituted with 1-5 substituents, wherein the substituents are the sameor different, and are chosen from methyl, ethyl, hydroxy, amino, cyanoand fluoro, aryl-C₁₋₃-alkyl, heteroaryl-C₁₋₃-alkyl,aryl-C₁₋₃-heteroalkyl, and heteroaryl-C₁₋₃-heteroalkyl, wherein the arylor heteroaryl groups are optionally substituted with 1-5 substituents Y,wherein each Y is the same or different, and is chosen from C₁₋₃-alkyl,C₁₋₃-alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio,trifluoromethoxy, nitro, amino, mono- or dialkyl(C₁₋₂)-amino, mono- ordialkyl(C₁₋₂)-amido, (C₁₋₃)-alkyl sulfonyl, dimethylsulfamido,C₁₋₃-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano,carbamoyl, sulfamoyl, phenyl, and acetyl, and 2-cyano-ethyl; R₂ ischosen from aryl and heteroaryl, each of which may be optionallysubstituted with 1-5 substituents Y as defined above; R₃ is chosen from:linear and branched C₃₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₅₋₁₀ bicycloalkyl,C₆₋₁₀ tricycloalkyl and C₈₋₁₁ tetracycloalkyl, each of which may beoptionally substituted with 1-5 substituents, wherein the substituentsare the same or different, and are chosen from methyl, ethyl, hydroxy,amino, and fluoro, C₃₋₈ cycloalkyl substituted with aryl and heteroaryl,wherein the aryl and heteroaryl are optionally substituted with 1-5substituents Y as defined above, 2,2,2-trifluoroethyl and 2-fluoroethyl,C₅₋₈ heterocycloalkyl, C₆₋₁₀ bicycloheteroalkyl, and C₇₋₁₀tricycloheteroalkyl, each of which may be optionally substituted with1-5 substituents, wherein the substituents are the same or different,and are chosen from methyl, ethyl, hydroxy, amino, and fluoro, C₃₋₈cycloalkyl-C₁₋₃-alkyl, C₅₋₁₀-bicycloalkyl-C₁₋₃-alkyl, andC₆₋₁₀-tricycloalkyl-C₁₋₃-alkyl, each of which may be optionallysubstituted with 1-5 substituents, wherein the substituents are the sameor different, and are chosen from methyl, ethyl, hydroxy, amino, andfluoro, branched and linear C₃₋₈ heterocycloalkyl-C₁₋₃-alkyl, C₅₋₁₀bicycloheteroalkyl-C₁₋₃-alkyl, and C₆₋₁₀ tricycloheteroalkyl-C₁₋₃-alkyl,each of which may be optionally substituted with 1-5 substituents,wherein the substituents are the same or different, and are chosen frommethyl, ethyl, hydroxy, amino, and fluoro, aryl and heteroaryl, each ofwhich may be optionally substituted with 1-5 substituents Y as definedabove, aryl-C₁₋₅-alkyl, heteroaryl-C₁₋₅-alkyl, and diaryl-C₁₋₅-alkyl,wherein the aryl or heteroaryl groups are optionally substituted with1-5 substituents Y as defined above, linear and branched C₄₋₈ alkenyland C₄₋₈ alkynyl, each of which may be optionally substituted with 1-3fluorine atoms, and branched and linear C₂₋₁₀ heteroalkyl, comprising1-2 heteroatoms chosen from N, O, or S; R₄ is chosen from hydrogen andC₁₋₄ alkyl; R₅ is chosen from hydrogen and C₁₋₂ alkyl, optionallysubstituted with 1-3 fluorine atoms; and R₆ is chosen from hydrogen andC₁₋₂ alkyl, optionally substituted with 1-3 fluorine atoms.
 2. Acompound according to claim 1, or a tautomer, stereoisomer, N-oxide, ora pharmacologically acceptable salt of any of the foregoing, wherein: R₁is chosen from: C₃₋₁₀ linear alkyl, C₄₋₁₀ branched alkyl, andC₅₋₈-cycloalkyl-C₁₋₅-alkyl, each of which may be optionally substitutedwith 1-3 substituents, wherein the substituents are the same ordifferent, and are chosen from methyl, ethyl, cyano, and fluoro;aryl-C₁₋₃-alkyl, wherein the aryl group is optionally substituted with1-3 substituents Y, wherein each Y is the same or different, and ischosen from C₁₋₃-alkyl, C₁₋₃-alkoxy, halogen, trifluoromethyl,trifluoro-methoxy, nitro, cyano, and phenyl, and 2-cyano-ethyl; R₂ ischosen from phenyl, thienyl, benzothienyl, and pyridyl, each of whichmay be optionally substituted with 1 or 2 substituents, wherein thesubstituents are the same or different, and are chosen from halogen,methyl, CF₃, OCH₃, and OCF₃; R₃ is chosen from: linear and branchedC₃₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₅₋₁₀ bicycloalkyl, and C₆₋₁₀tricycloalkyl, each of which may be optionally substituted with 1-3substituents, wherein the substituents are the same or different, andare chosen from methyl, ethyl, hydroxy, amino, fluoro, and aryl, C₅₋₈heterocycloalkyl optionally substituted with 1-5 substituents, whereinthe substituents are the same or different, and are chosen from methyl,ethyl, and fluoro, C₃₋₈ cycloalkyl-C₁₋₃-alkyl,C₅₋₁₀-bicycloalkyl-C₁₋₃-alkyl, and C₆₋₁₀-tricycloalkyl-C₁₋₃-alkyl, eachof which may be optionally substituted with 1-5 substituents, whereinthe substituents are the same or different, and are chosen from methyl,ethyl, and fluoro, aryl and heteroaryl, each of which may be optionallysubstituted with 1-5 substituents Y, wherein each Y is the same ordifferent, and is chosen from C₁₋₃-alkyl, C₁₋₃-alkoxy, halogen,trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, cyano,and phenyl, aryl-C₁₋₅-alkyl, heteroaryl-C₁₋₅-alkyl, anddiaryl-C₁₋₅-alkyl, wherein the aryl and heteroaryl groups are optionallysubstituted with 1-5 substituents, wherein the substituents are the sameor different, and are chosen from C₁₋₃-alkyl, C₁₋₃-alkoxy, halogen,trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, cyano,and phenyl, and branched and linear C₂₋₁₀ heteroalkyl, comprising 1-2heteroatoms chosen from N, O, and S; and R₄, R₅, and R₆ are as definedin claim
 1. 3. A compound according to claim 2, or a tautomer,stereoisomer, N-oxide, or a pharmacologically acceptable salt of any ofthe foregoing, wherein: R₁ is chosen from: C₃₋₈ linear alkyl, C₄₋₈branched alkyl, and C₅₋₆-cycloalkyl-C₁₋₅-alkyl, each of which may beoptionally substituted with 1-3 substituents, wherein the substituentsare the same or different, and are chosen from cyano and fluoro; andaryl-C₁₋₃-alkyl and 2-cyano-ethyl; R₂ is chosen from phenyl, thienyl,benzothienyl, and pyridyl, each of which may be optionally substitutedwith halogen, methyl, CF₃, OCH₃, and OCF₃; and R₃, R₄, R₅, and R₆ havethe meanings as defined in claim
 2. 4. A compound according to claim 3,or a tautomer, stereoisomer, N-oxide, or a pharmacologically acceptablesalt of any of the foregoing, wherein: R₁ is chosen from 2-cyano-ethyl,n-propyl, n-butyl, 4,4,4-trifluorobutyl, isobutyl, n-pentyl,cyclohexylmethyl, and phenethyl; R₂ is chosen from 2-fluorophenyl,3-(trifluoromethyl)phenyl, 3-chlorophenyl, 3-fluorophenyl,3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, benzothien-3-yl,pyrid-2-yl, thien-3-yl, and phenyl; R₃ is chosen from3-(trifluoromethyl)benzyl, 3-(trifluoromethyl)benzyl,1-(4-fluorophenyl)-1-methyl-ethyl, 1-phenyl-1-methyl-ethyl,1-phenyl-ethyl, 2-indanyl, 2-(4-fluorophenyl)-1,1-dimethyl-ethyl,2-(trifluoromethyl)benzyl, 2,2-dimethylpropyl, 2,2-diphenylethyl,2,2-diphenylpropyl, 2-methoxybenzyl, 2-phenyl-propyl,2-phenyl-trans-cyclopropyl, 2-trifluoromethyl)phenyl,3,4,5-trimethoxybenzyl, 3,4-dimethoxybenzyl, 3-fluorobenzyl,3-methoxybenzyl, 4-chlorobenzyl, 4-methoxybenzyl, 5-methyl-thiazol-2-yl,adamant-1-yl, adamant-2-yl, adamantylmethyl, benzyl, cycloheptyl,cyclohexylmethyl, cyclooctyl, endo-bicyclo[2.2.1]hept-2-yl,exo-bicyclo[2.2.1]hept-2-yl, indan-2-yl,N,2,2,6,6-pentamethylpiperidin-4-yl, naphth-1-yl,naphthalen-1-yl-methyl, noradamant-1-yl, pyridin-3-ylmethyl,quinolin-3-yl, tert-butyl, (1-ethyl)propyl,(1R,2S,5R)-rel-6,6-dimethylbicyclo[3.1.1.]heptan-2-methyl,(3-dimethylamino)-2,2-dimethylpropyl, (furan-2-yl)methyl,(pyridin-3-yl)-methyl, 1-(4-fluorophenyl)-1-methyl-ethyl,1-(adamant-1-yl)-ethyl, 1-phenyl-1-methyl-ethyl,2-(4-fluorophenyl)ethyl, 2-(7-methyl-indol-3-yl)ethyl,2-(indol-3-yl)ethyl, 2-(thien-2-yl)ethyl, 3-(trifluoromethyl)benzyl,3,3-diphenylpropyl, 3,4-difluorobenzyl, 4-(trifluoromethyl)benzyl,endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl,naphthalen-1-yl-methyl, benzyl, cyclohexylmethyl, cyclopentyl,methyl-N-(Naphthalen-1-yl-methyl), and phenyl; R₄ is chosen fromhydrogen and methyl; R₅ is chosen from hydrogen and methyl; and R₆ ishydrogen.
 5. A compound according to claim 1, or a tautomer,stereoisomer, N-oxide, or a pharmacologically acceptable salt of any ofthe foregoing, wherein said compound is an optically active enantiomer.6. A medicament, comprising a compound according to claim 1, or apharmacologically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising, a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier and/or at least one pharmaceutically acceptable auxiliarysubstance.
 8. A pharmaceutical composition according to claim 7, for thetreatment of multiple sclerosis, traumatic brain injury, pain, appetitedisorders, epilepsy, Alzheimer's disease, Tourette's syndrome, cerebralischaemia or gastrointestinal disorders.
 9. A pharmaceutical compositionaccording to claim 7, further comprising at least one additionaltherapeutic agent.
 10. A method of treating at least one disorder orcondition mediated by cannabinoid receptors in a mammal, comprisingadministering to said mammal, a therapeutically acceptable amount of acompound of formula (I), or a pharmaceutically acceptable salt thereof,wherein the disorder or condition is chosen from multiple sclerosis,traumatic brain injury, pain including chronic pain, neuropathic pain,acute pain and inflammatory pain, osteoporosis, appetite disorders,epilepsy, Alzheimer's disease, Tourette's syndrome, cerebral ischaemiaand gastrointestinal disorders.
 11. A compound of formula (X):

wherein: R₂ is chosen from aryl and heteroaryl, each of which may beoptionally substituted with 1-5 substituents Y as defined above; R₃ ishydrogen; R₄ is chosen from: C₆₋₁₀ bicycloalkyl and C₇₋₁₀ tricycloalkyl,each of which may be optionally substituted with 1-5 substituents,wherein the substituents are the same or different, and are chosen frommethyl, ethyl, hydroxyl, amino, and fluoro; and2-phenyl-1,1-dimethyl-ethyl, and 1-phenyl-1-methyl-ethyl, wherein thephenyl groups are optionally substituted with 1-5 substituents Y,wherein each Y is the same or different, and is chosen from C₁₋₃-alkyl,C₁₋₃-alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio,trifluoromethoxy, nitro, amino, mono- or dialkyl(C₁₋₂)-amino, mono- ordialkyl(C₁₋₂)-amido, (C₁₋₃)-alkyl sulfonyl, dimethylsulfamido,C₁₋₃-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano,carbamoyl, sulfamoyl, phenyl, and acetyl.